rs2228555

Variant names:

• chr2-227008279-T-C
• rs2228555
• NM_000092.5:c.4548A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-227008279-T-C
• chr2-227008279-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000092.5(COL4A4):​c.4548A>G​(p.Val1516Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 1,613,658 control chromosomes in the GnomAD database, including 229,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1516V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.58 (26184 hom., cov: 34)
  • Exomes 𝑓: 0.52 (203512 hom.)
• Consequence: COL4A4 NM_000092.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.31
• Publications: 30 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-227008279-T-C is Benign according to our data. Variant chr2-227008279-T-C is described in ClinVar as Benign. ClinVar VariationId is 255041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.4548A>G	p.Val1516Val	synonymous_variant	Exon 47 of 48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.4548A>G	p.Val1516Val	synonymous_variant	Exon 47 of 48	5	NM_000092.5	ENSP00000379866.3
COL4A4	ENST00000682098.1	c.190-40A>G		intron_variant	Intron 1 of 2			ENSP00000508331.1

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87919 AN: 152048 Hom.: 26138 Cov.: 34

Gnomad AFR AF: 0.727

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.532

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.543

GnomAD2 exomes AF: 0.557 AC: 138571 AN: 248564 AF XY: 0.556

Gnomad AFR exome AF: 0.734

Gnomad AMR exome AF: 0.581

Gnomad ASJ exome AF: 0.547

Gnomad EAS exome AF: 0.557

Gnomad FIN exome AF: 0.544

Gnomad NFE exome AF: 0.499

Gnomad OTH exome AF: 0.534

GnomAD4 exome AF: 0.524 AC: 766451 AN: 1461492 Hom.: 203512 Cov.: 65 AF XY: 0.527 AC XY: 383127 AN XY: 727034

African (AFR) AF: 0.734 AC: 24555 AN: 33476

American (AMR) AF: 0.578 AC: 25834 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 14331 AN: 26130

East Asian (EAS) AF: 0.576 AC: 22883 AN: 39694

South Asian (SAS) AF: 0.672 AC: 57985 AN: 86238

European-Finnish (FIN) AF: 0.545 AC: 29120 AN: 53408

Middle Eastern (MID) AF: 0.496 AC: 2860 AN: 5768

European-Non Finnish (NFE) AF: 0.501 AC: 556667 AN: 1111704

Other (OTH) AF: 0.534 AC: 32216 AN: 60382

GnomAD4 genome AF: 0.578 AC: 88023 AN: 152166 Hom.: 26184 Cov.: 34 AF XY: 0.578 AC XY: 42966 AN XY: 74382

African (AFR) AF: 0.727 AC: 30198 AN: 41528

American (AMR) AF: 0.544 AC: 8313 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 1847 AN: 3472

East Asian (EAS) AF: 0.569 AC: 2945 AN: 5176

South Asian (SAS) AF: 0.674 AC: 3253 AN: 4828

European-Finnish (FIN) AF: 0.536 AC: 5668 AN: 10578

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.502 AC: 34143 AN: 67980

Other (OTH) AF: 0.542 AC: 1144 AN: 2110

Alfa AF: 0.537 Hom.: 56389

Bravo AF: 0.584

Asia WGS AF: 0.639 AC: 2222 AN: 3478

EpiCase AF: 0.480

EpiControl AF: 0.492

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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.Val1516Val in exon 47 of COL4A4: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wi thin the splice consensus sequence, and has been identified in 77.61% (1026/1322 ) of African chromosomes by the 1000 Genomes Project (Phase 3; dbSNP rs2228555). -

Nov 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

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 77% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 72. Only high quality variants are reported. -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alport syndrome Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

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
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.9
DANN	Benign	0.67
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2228555; hg19: chr2-227872995; COSMIC: COSV61631066;