chr2-227010441-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_000092.5(COL4A4):​c.4394G>A​(p.Gly1465Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,458 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000043 ( 1 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

12
4
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:7

Conservation

PhyloP100: 7.86

Publications

8 publications found
Variant links:
Genes affected
COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]
COL4A4 Gene-Disease associations (from GenCC):
  • autosomal recessive Alport syndrome
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Myriad Women’s Health
  • Alport syndrome
    Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
  • hematuria, benign familial, 1
    Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
  • autosomal dominant Alport syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.907
PP5
Variant 2-227010441-C-T is Pathogenic according to our data. Variant chr2-227010441-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 523324.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL4A4NM_000092.5 linkc.4394G>A p.Gly1465Asp missense_variant Exon 46 of 48 ENST00000396625.5 NP_000083.3 P53420

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL4A4ENST00000396625.5 linkc.4394G>A p.Gly1465Asp missense_variant Exon 46 of 48 5 NM_000092.5 ENSP00000379866.3 P53420
COL4A4ENST00000682098.1 linkc.61G>A p.Ala21Thr missense_variant Exon 1 of 3 ENSP00000508331.1 A0A804HLF6

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152252
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000725
AC:
18
AN:
248434
AF XY:
0.0000816
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000465
Gnomad NFE exome
AF:
0.0000355
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000431
AC:
63
AN:
1461206
Hom.:
1
Cov.:
32
AF XY:
0.0000523
AC XY:
38
AN XY:
726812
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33444
American (AMR)
AF:
0.0000224
AC:
1
AN:
44672
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26082
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.000487
AC:
42
AN:
86154
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53404
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5740
European-Non Finnish (NFE)
AF:
0.0000162
AC:
18
AN:
1111656
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60360
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
4
8
11
15
19
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152252
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74382
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41458
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5204
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000735
AC:
5
AN:
68046
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000108
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000911
AC:
11
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal recessive Alport syndrome Pathogenic:3Uncertain:1
-
Neuberg Centre For Genomic Medicine, NCGM
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The missense variant c.4394G>A(p.Gly1465Asp) in COL4A4 gene has been observed in heterozygous state in individual(s) with clinical features of autosomal dominant Alport syndrome, autosomal recessive Alport syndrome, and basement membrane disease (Kopadze et. al., 2021; Papazachariou et. al., 2017). It has also been observed to segregate with disease in related individuals. This variant is almost always reported in cis with the COL4A4 variant c.2320G>C, p.(Gly774Arg) in individuals and families with both dominant and recessive forms of Alport syndrome (Goka et. al., 2021; Papazachariou et. al., 2017). The p.Gly1465Asp variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.007% in gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic / Likely pathogenic / Uncertain Significance. The amino acid change p.Gly1465Asp in COL4A4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 1465 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies will be required to confirm the pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic. -

Apr 02, 2018
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 01, 2024
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:curation

- -

Sep 20, 2023
3billion
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.95 (>=0.6, sensitivity 0.68 and specificity 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000523324 /PMID: 24033287).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 28632965).The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 28632965). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1Uncertain:2
Jul 27, 2021
Mayo Clinic Laboratories, Mayo Clinic
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

BP2, PP3, PM2_supporting -

Jun 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

COL4A4: PM2, PS4:Moderate -

Nov 25, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1465 of the COL4A4 protein (p.Gly1465Asp). This variant is present in population databases (rs533297350, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of autosomal dominant Alport syndrome, autosomal recessive Alport syndrome, and basement membrane disease (PMID: 24033287, 26934356, 28632965, 34584596). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 523324). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL4A4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Alport syndrome Uncertain:3
Jan 09, 2018
Sydney Genome Diagnostics, Children's Hospital Westmead
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

This individual is also homozygous for the c.4394G>A p.(Gly1465Asp) variant in the COL4A4 gene. To our knowledge, this variant has not been previously reported in the literature or any disease specific databases. The c.4394G>A variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.006% (19 out of 275976 alleles). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster all suggest that this variant is likely to be pathogenic. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines. -

Mar 30, 2023
Molecular Genetics, Royal Melbourne Hospital
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change in COL4A4 is predicted to replace glycine with aspartic acid at codon 1465 (p.(Gly1465Asp)). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in the collagen IV NC1 domain. There is a moderate physicochemical difference between glycine and aspartic acid. The highest population minor allele frequency in gnomAD v2.1 is 0.04% (13/30,488 alleles) in the South Asian population, which is lower than the credible allele frequency for recessive Alport syndrome. This variant is almost always reported in cis with the likely pathogenic variant c.2320G>C, p.(Gly774Arg) in individuals and families with both dominant and recessive forms of Alport syndrome (PMID: 24033287, 26934356, 28632965, 29496980, 33048202, 33838161). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3. -

Mar 31, 2022
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Loss of function is a known mechanism of disease for this gene and is associated with COL4A4-related nephropathy. Dominant negative is a suspected mechanism of disease for this gene as it is a structural protein (PMID: 12028435, 24046192). (I) 0108 - This gene is associated with both recessive and dominant disease. Alport syndrome typically has biallelic inheritance, although rare cases of monoallelic inheritance have been reported. TBMN and focal segmental glomerulosclerosis (FSGS) are associated with autosomal dominant inheritance (OMIM, PMID: 28704582, 16467446, 17942953). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 19 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated collagen IV NC1 domain (PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been classified as likely pathogenic and a VUS by diagnostic laboratories in ClinVar, likely because it has been reported to be in cis with a known pathogenic variant (p.(Gly774Arg)). However, a single family has been reported with Alports disease, where no other variant was detected (ClinVar; PMID: 28632965, 26934356, 24033287). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Benign familial hematuria Pathogenic:1
May 04, 2022
Mendelics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hematuria;C0020538:Hypertensive disorder;C0027092:Myopia;C0033687:Proteinuria;C1384666:Hearing impairment Pathogenic:1
Jan 01, 2017
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Autosomal recessive Alport syndrome;CN376803:Hematuria, benign familial, 1 Uncertain:1
-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PM2_Supporting+PS4_Supporting+PP3+PP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.31
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.50
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.76
T
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.91
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
H
PhyloP100
7.9
PrimateAI
Uncertain
0.66
T
PROVEAN
Pathogenic
-5.0
D
REVEL
Pathogenic
0.95
Sift
Uncertain
0.0070
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.97
MutPred
0.67
Gain of sheet (P = 0.1208);
MVP
0.94
MPC
0.18
ClinPred
0.82
D
GERP RS
5.7
PromoterAI
0.030
Neutral
Varity_R
0.54
gMVP
0.94
Mutation Taster
=7/93
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs533297350; hg19: chr2-227875157; COSMIC: COSV61633254; API