rs3769641

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000092.5(COL4A4):c.2384-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0859 in 1,613,482 control chromosomes in the GnomAD database, including 6,350 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.076 ( 471 hom., cov: 33)

Exomes 𝑓: 0.087 ( 5879 hom. )

Consequence

COL4A4
NM_000092.5 splice_region, intron

Scores

Splicing: ADA: 0.01959

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.98

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 2-227057605-A-G is Benign according to our data. Variant chr2-227057605-A-G is described in ClinVar as [Benign]. Clinvar id is 255020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227057605-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A4	NM_000092.5 link	c.2384-5T>C		splice_region_variant, intron_variant		ENST00000396625.5	NP_000083.3	P53420

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 link	c.2384-5T>C		splice_region_variant, intron_variant		5	NM_000092.5	ENSP00000379866.3		P53420

Frequencies

GnomAD3 genomes

AF:

0.0759

AC:

11548

AN:

152148

Hom.:

469

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0494

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0709

Gnomad ASJ

AF:

0.0717

Gnomad EAS

AF:

0.183

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.0618

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.0847

Gnomad OTH

AF:

0.0837

GnomAD3 exomes

AF:

0.0847

AC:

21109

AN:

249150

Hom.:

1021

AF XY:

0.0880

AC XY:

11896

AN XY:

135142

show subpopulations

Gnomad AFR exome

AF:

0.0456

Gnomad AMR exome

AF:

0.0493

Gnomad ASJ exome

AF:

0.0767

Gnomad EAS exome

AF:

0.168

Gnomad SAS exome

AF:

0.115

Gnomad FIN exome

AF:

0.0622

Gnomad NFE exome

AF:

0.0844

Gnomad OTH exome

AF:

0.0884

GnomAD4 exome

AF:

0.0869

AC:

126974

AN:

1461216

Hom.:

5879

Cov.:

AF XY:

0.0881

AC XY:

64054

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.0490

Gnomad4 AMR exome

AF:

0.0506

Gnomad4 ASJ exome

AF:

0.0736

Gnomad4 EAS exome

AF:

0.175

Gnomad4 SAS exome

AF:

0.111

Gnomad4 FIN exome

AF:

0.0635

Gnomad4 NFE exome

AF:

0.0856

Gnomad4 OTH exome

AF:

0.0885

GnomAD4 genome

AF:

0.0760

AC:

11567

AN:

152266

Hom.:

471

Cov.:

AF XY:

0.0759

AC XY:

5654

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0495

Gnomad4 AMR

AF:

0.0707

Gnomad4 ASJ

AF:

0.0717

Gnomad4 EAS

AF:

0.183

Gnomad4 SAS

AF:

0.119

Gnomad4 FIN

AF:

0.0618

Gnomad4 NFE

AF:

0.0847

Gnomad4 OTH

AF:

0.0889

Alfa

AF:

0.0844

Hom.:

1440

Bravo

AF:

0.0740

Asia WGS

AF:

0.150

AC:

519

AN:

3478

EpiCase

AF:

0.0858

EpiControl

AF:

0.0938

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	c.2384-5T>C in intron 28 of COL4A4: This variant is not expected to have clinica l significance because a T>C change at this position does not diverge from the s plice consensus sequence and is therefore unlikely to impact splicing. It has be en identified in 16.50% (1412/8558) of East Asian chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3769641). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Alport syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.020

dbscSNV1_RF

Benign

0.18

SpliceAI score (max)

0.41

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.41

Position offset: -32

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over