2-227022057-A-G

Variant names:

• chr2-227022057-A-G
• rs3752895
• NM_000092.5:c.4207T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000092.5(COL4A4):​c.4207T>C​(p.Ser1403Pro) variant causes a missense change. The variant allele was found at a frequency of 0.447 in 1,612,828 control chromosomes in the GnomAD database, including 164,328 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.49 (19177 hom., cov: 31)
  • Exomes 𝑓: 0.44 (145151 hom.)
• Consequence: COL4A4 NM_000092.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.74
• Publications: 44 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.318786E-5).
• BP6: Variant 2-227022057-A-G is Benign according to our data. Variant chr2-227022057-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.4207T>C	p.Ser1403Pro	missense_variant	Exon 44 of 48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.4207T>C	p.Ser1403Pro	missense_variant	Exon 44 of 48	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.494 AC: 74967 AN: 151788 Hom.: 19134 Cov.: 31

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.459

GnomAD2 exomes AF: 0.477 AC: 118999 AN: 249310 AF XY: 0.473

Gnomad AFR exome AF: 0.642

Gnomad AMR exome AF: 0.538

Gnomad ASJ exome AF: 0.509

Gnomad EAS exome AF: 0.396

Gnomad FIN exome AF: 0.496

Gnomad NFE exome AF: 0.422

Gnomad OTH exome AF: 0.457

GnomAD4 exome AF: 0.442 AC: 645388 AN: 1460922 Hom.: 145151 Cov.: 38 AF XY: 0.443 AC XY: 322051 AN XY: 726778

African (AFR) AF: 0.637 AC: 21321 AN: 33454

American (AMR) AF: 0.533 AC: 23851 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 13454 AN: 26132

East Asian (EAS) AF: 0.411 AC: 16301 AN: 39694

South Asian (SAS) AF: 0.559 AC: 48237 AN: 86216

European-Finnish (FIN) AF: 0.495 AC: 26430 AN: 53406

Middle Eastern (MID) AF: 0.404 AC: 2331 AN: 5768

European-Non Finnish (NFE) AF: 0.420 AC: 466368 AN: 1111180

Other (OTH) AF: 0.449 AC: 27095 AN: 60362

GnomAD4 genome AF: 0.494 AC: 75056 AN: 151906 Hom.: 19177 Cov.: 31 AF XY: 0.494 AC XY: 36664 AN XY: 74228

African (AFR) AF: 0.630 AC: 26102 AN: 41444

American (AMR) AF: 0.480 AC: 7341 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1710 AN: 3468

East Asian (EAS) AF: 0.388 AC: 1989 AN: 5122

South Asian (SAS) AF: 0.550 AC: 2645 AN: 4810

European-Finnish (FIN) AF: 0.489 AC: 5151 AN: 10524

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.422 AC: 28675 AN: 67938

Other (OTH) AF: 0.453 AC: 953 AN: 2104

Alfa AF: 0.444 Hom.: 53355

Bravo AF: 0.500

TwinsUK AF: 0.421 AC: 1560

ALSPAC AF: 0.415 AC: 1598

ESP6500AA AF: 0.608 AC: 2276

ESP6500EA AF: 0.419 AC: 3440

ExAC AF: 0.476 AC: 57469

Asia WGS AF: 0.483 AC: 1682 AN: 3478

EpiCase AF: 0.401

EpiControl AF: 0.407

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Nov 29, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.Ser1403Pro in exon 44 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 68.91% (911/1322) of African chr omosomes by the 1000 Genomes Project (Phase 3; dbSNP rs3752895).

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.

not provided Benign:3

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Alport syndrome Benign:2

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.

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.33
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.0094	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.000073	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.0	N
PhyloP100		3.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	3.2	N
REVEL	Benign	0.23
Sift	Benign	0.78	T
Sift4G	Benign	1.0	T
Vest4		0.071
ClinPred		0.0068	T
GERP RS		5.6
Varity_R		0.066
gMVP		0.18
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: rs3752895; hg19: chr2-227886773; COSMIC: COSV61629628;