rs2228557

Positions:

• chr2-227007466-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000092.5(COL4A4):​c.4932C>T​(p.Phe1644=) 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:10
• Conservation: PhyloP100: 1.27

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 255043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227007466-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.4932C>T	p.Phe1644=	synonymous_variant	48/48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.4932C>T	p.Phe1644=	synonymous_variant	48/48	5	NM_000092.5	ENSP00000379866	P1
COL4A4	ENST00000682098.1	c.534C>T	p.Phe178=	synonymous_variant	3/3			ENSP00000508331

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

GnomAD3 exomes AF: 0.467 AC: 116579 AN: 249438 Hom.: 28005 AF XY: 0.465 AC XY: 62918 AN XY: 135350

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 SAS exome AF: 0.578

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

Gnomad4 AFR exome AF: 0.600

Gnomad4 AMR exome AF: 0.524

Gnomad4 ASJ exome AF: 0.464

Gnomad4 EAS exome AF: 0.403

Gnomad4 SAS exome AF: 0.578

Gnomad4 FIN exome AF: 0.483

Gnomad4 NFE exome AF: 0.409

Gnomad4 OTH exome AF: 0.435

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

Gnomad4 AFR AF: 0.603

Gnomad4 AMR AF: 0.466

Gnomad4 ASJ AF: 0.447

Gnomad4 EAS AF: 0.386

Gnomad4 SAS AF: 0.574

Gnomad4 FIN AF: 0.477

Gnomad4 NFE AF: 0.411

Gnomad4 OTH AF: 0.435

Alfa AF: 0.422 Hom.: 32575

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	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). -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 03, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Alport syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.8
DANN	Benign	0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228557; hg19: chr2-227872182; COSMIC: COSV61629620;