rs2228557

Variant names:

• chr2-227007466-G-A
• rs2228557
• NM_000092.5:c.4932C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000092.5(COL4A4):​c.4932C>T​(p.Phe1644Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,613,496 control chromosomes in the GnomAD database, including 156,375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17965 hom., cov: 33)
  • Exomes 𝑓: 0.43 (138410 hom.)
• Consequence: COL4A4 NM_000092.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.27
• Publications: 39 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-227007466-G-A is Benign according to our data. Variant chr2-227007466-G-A is described in ClinVar as Benign. ClinVar VariationId is 255043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.4932C>T	p.Phe1644Phe	synonymous_variant	Exon 48 of 48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.4932C>T	p.Phe1644Phe	synonymous_variant	Exon 48 of 48	5	NM_000092.5	ENSP00000379866.3
COL4A4	ENST00000682098.1	c.534C>T	p.Phe178Phe	synonymous_variant	Exon 3 of 3			ENSP00000508331.1

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72718 AN: 151926 Hom.: 17924 Cov.: 33

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.466

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.477

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.441

GnomAD2 exomes AF: 0.467 AC: 116579 AN: 249438 AF XY: 0.465

Gnomad AFR exome AF: 0.607

Gnomad AMR exome AF: 0.530

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.394

Gnomad FIN exome AF: 0.484

Gnomad NFE exome AF: 0.410

Gnomad OTH exome AF: 0.442

GnomAD4 exome AF: 0.431 AC: 629995 AN: 1461452 Hom.: 138410 Cov.: 65 AF XY: 0.434 AC XY: 315231 AN XY: 727092

African (AFR) AF: 0.600 AC: 20091 AN: 33480

American (AMR) AF: 0.524 AC: 23224 AN: 44356

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 12132 AN: 26136

East Asian (EAS) AF: 0.403 AC: 15997 AN: 39700

South Asian (SAS) AF: 0.578 AC: 49866 AN: 86254

European-Finnish (FIN) AF: 0.483 AC: 25800 AN: 53406

Middle Eastern (MID) AF: 0.371 AC: 2138 AN: 5762

European-Non Finnish (NFE) AF: 0.409 AC: 454473 AN: 1111962

Other (OTH) AF: 0.435 AC: 26274 AN: 60396

GnomAD4 genome AF: 0.479 AC: 72807 AN: 152044 Hom.: 17965 Cov.: 33 AF XY: 0.479 AC XY: 35588 AN XY: 74310

African (AFR) AF: 0.603 AC: 24982 AN: 41454

American (AMR) AF: 0.466 AC: 7125 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1550 AN: 3468

East Asian (EAS) AF: 0.386 AC: 1997 AN: 5174

South Asian (SAS) AF: 0.574 AC: 2770 AN: 4826

European-Finnish (FIN) AF: 0.477 AC: 5042 AN: 10572

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.411 AC: 27963 AN: 67960

Other (OTH) AF: 0.435 AC: 918 AN: 2110

Alfa AF: 0.432 Hom.: 51446

Bravo AF: 0.482

Asia WGS AF: 0.487 AC: 1695 AN: 3478

EpiCase AF: 0.389

EpiControl AF: 0.394

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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.Phe1644Phe in exon 48 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 63.69% (842/1322) of African chromosomes by the 1000 Genomes Project (Phase 3; dbSNP rs2228557). -

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. -

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. -

-

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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

Alport syndrome Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

Autosomal recessive Alport syndrome Benign:1

Jul 30, 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	-0.46
CADD	Benign	9.8
DANN	Benign	0.81
PhyloP100		1.3
Mutation Taster		=99/1	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: rs2228557; hg19: chr2-227872182; COSMIC: COSV61629620;