rs1800519

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000092.5(COL4A4):​c.2717-5A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,613,524 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.012 ( 21 hom., cov: 33)
Exomes 𝑓: 0.015 ( 227 hom. )

Consequence

COL4A4
NM_000092.5 splice_region, intron

Scores

2
Splicing: ADA: 0.00001587
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11

Conservation

PhyloP100: -0.296
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 -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0117 (1785/152292) while in subpopulation NFE AF= 0.0191 (1302/68028). AF 95% confidence interval is 0.0183. There are 21 homozygotes in gnomad4. There are 833 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 21 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL4A4NM_000092.5 linkc.2717-5A>T splice_region_variant, intron_variant Intron 30 of 47 ENST00000396625.5 NP_000083.3 P53420

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL4A4ENST00000396625.5 linkc.2717-5A>T splice_region_variant, intron_variant Intron 30 of 47 5 NM_000092.5 ENSP00000379866.3 P53420

Frequencies

GnomAD3 genomes
AF:
0.0117
AC:
1784
AN:
152174
Hom.:
21
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00280
Gnomad AMI
AF:
0.00330
Gnomad AMR
AF:
0.0156
Gnomad ASJ
AF:
0.0150
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00311
Gnomad FIN
AF:
0.00217
Gnomad MID
AF:
0.0253
Gnomad NFE
AF:
0.0191
Gnomad OTH
AF:
0.0115
GnomAD3 exomes
AF:
0.0114
AC:
2818
AN:
247698
Hom.:
30
AF XY:
0.0119
AC XY:
1606
AN XY:
134508
show subpopulations
Gnomad AFR exome
AF:
0.00210
Gnomad AMR exome
AF:
0.0110
Gnomad ASJ exome
AF:
0.0120
Gnomad EAS exome
AF:
0.000168
Gnomad SAS exome
AF:
0.00350
Gnomad FIN exome
AF:
0.00307
Gnomad NFE exome
AF:
0.0180
Gnomad OTH exome
AF:
0.0153
GnomAD4 exome
AF:
0.0152
AC:
22177
AN:
1461232
Hom.:
227
Cov.:
31
AF XY:
0.0151
AC XY:
10942
AN XY:
726896
show subpopulations
Gnomad4 AFR exome
AF:
0.00425
Gnomad4 AMR exome
AF:
0.0106
Gnomad4 ASJ exome
AF:
0.0132
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.00357
Gnomad4 FIN exome
AF:
0.00290
Gnomad4 NFE exome
AF:
0.0177
Gnomad4 OTH exome
AF:
0.0149
GnomAD4 genome
AF:
0.0117
AC:
1785
AN:
152292
Hom.:
21
Cov.:
33
AF XY:
0.0112
AC XY:
833
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.00282
Gnomad4 AMR
AF:
0.0156
Gnomad4 ASJ
AF:
0.0150
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00311
Gnomad4 FIN
AF:
0.00217
Gnomad4 NFE
AF:
0.0191
Gnomad4 OTH
AF:
0.0114
Alfa
AF:
0.0170
Hom.:
7
Bravo
AF:
0.0122
Asia WGS
AF:
0.00491
AC:
17
AN:
3478
EpiCase
AF:
0.0225
EpiControl
AF:
0.0226

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:11
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:6
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 31, 2018
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

COL4A4: BP4, BS1, BS2 -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

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

- -

Jun 12, 2018
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15618242) -

not specified Benign:2
-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Alport syndrome Benign:2
Oct 29, 2019
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Autosomal recessive Alport syndrome Uncertain:1
Mar 11, 2020
Medical Genetics, University of Parma
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Benign familial hematuria;C5882663:Autosomal dominant Alport syndrome Uncertain:1
Mar 11, 2020
Medical Genetics, University of Parma
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis Benign:1
Aug 20, 2022
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
0.15
DANN
Benign
0.47

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000016
dbscSNV1_RF
Benign
0.0
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: rs1800519; hg19: chr2-227919458; API