rs2228556

Variant names:

• chr2-227027903-C-T
• rs2228556
• NM_000092.5:c.4080G>A

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.4080G>A​(p.Pro1360Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 1,601,552 control chromosomes in the GnomAD database, including 159,533 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (16859 hom., cov: 31)
  • Exomes 𝑓: 0.44 (142674 hom.)
• Consequence: COL4A4 NM_000092.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001429
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.529
• Publications: 20 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=-0.52).
• BP6: Variant 2-227027903-C-T is Benign according to our data. Variant chr2-227027903-C-T is described in ClinVar as Benign. ClinVar VariationId is 255036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.529 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.4080G>A	p.Pro1360Pro	splice_region_variant, synonymous_variant	Exon 42 of 48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.4080G>A	p.Pro1360Pro	splice_region_variant, synonymous_variant	Exon 42 of 48	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.468 AC: 71052 AN: 151816 Hom.: 16825 Cov.: 31

Gnomad AFR AF: 0.533

Gnomad AMI AF: 0.403

Gnomad AMR AF: 0.469

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.496

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.439

GnomAD2 exomes AF: 0.472 AC: 117495 AN: 248986 AF XY: 0.469

Gnomad AFR exome AF: 0.540

Gnomad AMR exome AF: 0.534

Gnomad ASJ exome AF: 0.510

Gnomad EAS exome AF: 0.398

Gnomad FIN exome AF: 0.499

Gnomad NFE exome AF: 0.426

Gnomad OTH exome AF: 0.455

GnomAD4 exome AF: 0.440 AC: 637409 AN: 1449618 Hom.: 142674 Cov.: 30 AF XY: 0.441 AC XY: 318677 AN XY: 721854

African (AFR) AF: 0.531 AC: 17597 AN: 33120

American (AMR) AF: 0.529 AC: 23599 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 13444 AN: 26034

East Asian (EAS) AF: 0.403 AC: 15961 AN: 39622

South Asian (SAS) AF: 0.553 AC: 47463 AN: 85898

European-Finnish (FIN) AF: 0.499 AC: 26626 AN: 53368

Middle Eastern (MID) AF: 0.397 AC: 2284 AN: 5746

European-Non Finnish (NFE) AF: 0.421 AC: 463903 AN: 1101214

Other (OTH) AF: 0.442 AC: 26532 AN: 59966

GnomAD4 genome AF: 0.468 AC: 71131 AN: 151934 Hom.: 16859 Cov.: 31 AF XY: 0.470 AC XY: 34866 AN XY: 74258

African (AFR) AF: 0.534 AC: 22119 AN: 41434

American (AMR) AF: 0.470 AC: 7173 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1719 AN: 3468

East Asian (EAS) AF: 0.387 AC: 1999 AN: 5160

South Asian (SAS) AF: 0.546 AC: 2630 AN: 4818

European-Finnish (FIN) AF: 0.496 AC: 5213 AN: 10518

Middle Eastern (MID) AF: 0.408 AC: 119 AN: 292

European-Non Finnish (NFE) AF: 0.425 AC: 28882 AN: 67958

Other (OTH) AF: 0.433 AC: 911 AN: 2102

Alfa AF: 0.437 Hom.: 22782

Bravo AF: 0.470

Asia WGS AF: 0.475 AC: 1656 AN: 3478

EpiCase AF: 0.403

EpiControl AF: 0.411

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

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.Pro1360Pro in exon 42 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 55.67% (9183/16494) of South Asi an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs2228556). -

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 56% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 52. Only high quality variants are reported. -

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. -

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 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome Benign:1

Oct 14, 2021

Fulgent Genetics, Fulgent Genetics

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	-0.52
CADD	Benign	11
DANN	Benign	0.41
PhyloP100		0.53
Mutation Taster		=69/31	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.026
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: rs2228556; hg19: chr2-227892619; COSMIC: COSV61632094;