2-227022057-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000092.5(COL4A4):​c.4207T>C​(p.Ser1403Pro) variant causes a missense change. The variant allele was found at a frequency of 0.447 in 1,612,828 control chromosomes in the GnomAD database, including 164,328 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 19177 hom., cov: 31)
Exomes 𝑓: 0.44 ( 145151 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 3.74
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=7.318786E-5).
BP6
Variant 2-227022057-A-G is Benign according to our data. Variant chr2-227022057-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 255038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227022057-A-G is described in Lovd as [Benign]. Variant chr2-227022057-A-G is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL4A4NM_000092.5 linkc.4207T>C p.Ser1403Pro missense_variant Exon 44 of 48 ENST00000396625.5 NP_000083.3 P53420

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL4A4ENST00000396625.5 linkc.4207T>C p.Ser1403Pro missense_variant Exon 44 of 48 5 NM_000092.5 ENSP00000379866.3 P53420

Frequencies

GnomAD3 genomes
AF:
0.494
AC:
74967
AN:
151788
Hom.:
19134
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.629
Gnomad AMI
AF:
0.404
Gnomad AMR
AF:
0.480
Gnomad ASJ
AF:
0.493
Gnomad EAS
AF:
0.388
Gnomad SAS
AF:
0.550
Gnomad FIN
AF:
0.489
Gnomad MID
AF:
0.424
Gnomad NFE
AF:
0.422
Gnomad OTH
AF:
0.459
GnomAD3 exomes
AF:
0.477
AC:
118999
AN:
249310
Hom.:
29113
AF XY:
0.473
AC XY:
64022
AN XY:
135304
show subpopulations
Gnomad AFR exome
AF:
0.642
Gnomad AMR exome
AF:
0.538
Gnomad ASJ exome
AF:
0.509
Gnomad EAS exome
AF:
0.396
Gnomad SAS exome
AF:
0.559
Gnomad FIN exome
AF:
0.496
Gnomad NFE exome
AF:
0.422
Gnomad OTH exome
AF:
0.457
GnomAD4 exome
AF:
0.442
AC:
645388
AN:
1460922
Hom.:
145151
Cov.:
38
AF XY:
0.443
AC XY:
322051
AN XY:
726778
show subpopulations
Gnomad4 AFR exome
AF:
0.637
Gnomad4 AMR exome
AF:
0.533
Gnomad4 ASJ exome
AF:
0.515
Gnomad4 EAS exome
AF:
0.411
Gnomad4 SAS exome
AF:
0.559
Gnomad4 FIN exome
AF:
0.495
Gnomad4 NFE exome
AF:
0.420
Gnomad4 OTH exome
AF:
0.449
GnomAD4 genome
AF:
0.494
AC:
75056
AN:
151906
Hom.:
19177
Cov.:
31
AF XY:
0.494
AC XY:
36664
AN XY:
74228
show subpopulations
Gnomad4 AFR
AF:
0.630
Gnomad4 AMR
AF:
0.480
Gnomad4 ASJ
AF:
0.493
Gnomad4 EAS
AF:
0.388
Gnomad4 SAS
AF:
0.550
Gnomad4 FIN
AF:
0.489
Gnomad4 NFE
AF:
0.422
Gnomad4 OTH
AF:
0.453
Alfa
AF:
0.433
Hom.:
36233
Bravo
AF:
0.500
TwinsUK
AF:
0.421
AC:
1560
ALSPAC
AF:
0.415
AC:
1598
ESP6500AA
AF:
0.608
AC:
2276
ESP6500EA
AF:
0.419
AC:
3440
ExAC
AF:
0.476
AC:
57469
Asia WGS
AF:
0.483
AC:
1682
AN:
3478
EpiCase
AF:
0.401
EpiControl
AF:
0.407

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 29, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 21, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Ser1403Pro in exon 44 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 68.91% (911/1322) of African chr omosomes by the 1000 Genomes Project (Phase 3; dbSNP rs3752895). -

Jul 15, 2024
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 70% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 65. Only high quality variants are reported. -

May 09, 2017
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3
Apr 03, 2017
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Alport syndrome Benign:2
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Autosomal recessive Alport syndrome Benign:1
Jul 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.043
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
19
DANN
Benign
0.33
DEOGEN2
Benign
0.060
T
Eigen
Benign
-0.65
Eigen_PC
Benign
-0.39
FATHMM_MKL
Benign
0.0094
N
LIST_S2
Benign
0.42
T
MetaRNN
Benign
0.000073
T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
-2.0
N
PrimateAI
Benign
0.42
T
PROVEAN
Benign
3.2
N
REVEL
Benign
0.23
Sift
Benign
0.78
T
Sift4G
Benign
1.0
T
Polyphen
0.0
B
Vest4
0.071
MPC
0.18
ClinPred
0.0068
T
GERP RS
5.6
Varity_R
0.066
gMVP
0.18

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs3752895; hg19: chr2-227886773; COSMIC: COSV61629628; API