rs3769641

Variant names:

• chr2-227057605-A-G
• rs3769641
• NM_000092.5:c.2384-5T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-227057605-A-G
• chr2-227057605-A-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

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
• Publications: 16 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 255020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.2384-5T>C		splice_region_variant, intron_variant	Intron 28 of 47	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.2384-5T>C		splice_region_variant, intron_variant	Intron 28 of 47	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.0759 AC: 11548 AN: 152148 Hom.: 469 Cov.: 33

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

GnomAD2 exomes AF: 0.0847 AC: 21109 AN: 249150 AF XY: 0.0880

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 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.: 34 AF XY: 0.0881 AC XY: 64054 AN XY: 726898

African (AFR) AF: 0.0490 AC: 1641 AN: 33472

American (AMR) AF: 0.0506 AC: 2262 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0736 AC: 1924 AN: 26134

East Asian (EAS) AF: 0.175 AC: 6964 AN: 39688

South Asian (SAS) AF: 0.111 AC: 9581 AN: 86192

European-Finnish (FIN) AF: 0.0635 AC: 3389 AN: 53390

Middle Eastern (MID) AF: 0.123 AC: 709 AN: 5768

European-Non Finnish (NFE) AF: 0.0856 AC: 95163 AN: 1111488

Other (OTH) AF: 0.0885 AC: 5341 AN: 60378

GnomAD4 genome AF: 0.0760 AC: 11567 AN: 152266 Hom.: 471 Cov.: 33 AF XY: 0.0759 AC XY: 5654 AN XY: 74444

African (AFR) AF: 0.0495 AC: 2057 AN: 41570

American (AMR) AF: 0.0707 AC: 1082 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0717 AC: 249 AN: 3472

East Asian (EAS) AF: 0.183 AC: 946 AN: 5166

South Asian (SAS) AF: 0.119 AC: 576 AN: 4828

European-Finnish (FIN) AF: 0.0618 AC: 656 AN: 10618

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.0847 AC: 5759 AN: 67998

Other (OTH) AF: 0.0889 AC: 188 AN: 2114

Alfa AF: 0.0823 Hom.: 2082

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

Submissions by phenotype

not specified Benign:3

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Aug 21, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 02, 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 13, 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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Benign	0.74
PhyloP100		3.0
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3769641; hg19: chr2-227922321;