rs2272205

chr2-227051208-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000092.5(COL4A4):c.2969-50A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0923 in 1,593,442 control chromosomes in the GnomAD database, including 7,208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (539 hom., cov: 32)
  • Exomes 𝑓: 0.094 (6669 hom.)
• Consequence: COL4A4 NM_000092.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.894

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-227051208-T-C is Benign according to our data. Variant chr2-227051208-T-C is described in ClinVar as [Benign]. Clinvar id is 682773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227051208-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A4	NM_000092.5	c.2969-50A>G		intron_variant		ENST00000396625.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A4	ENST00000396625.5	c.2969-50A>G		intron_variant		5	NM_000092.5	P1

Frequencies

GnomAD3 genomes AF: 0.0798 AC: 12127 AN: 152062 Hom.: 537 Cov.: 32

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0732

Gnomad ASJ AF: 0.0851

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.0621

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0917

Gnomad OTH AF: 0.0880

GnomAD3 exomes AF: 0.0906 AC: 22490 AN: 248274 Hom.: 1163 AF XY: 0.0944 AC XY: 12730 AN XY: 134826

Gnomad AFR exome AF: 0.0442

Gnomad AMR exome AF: 0.0515

Gnomad ASJ exome AF: 0.0878

Gnomad EAS exome AF: 0.167

Gnomad SAS exome AF: 0.129

Gnomad FIN exome AF: 0.0636

Gnomad NFE exome AF: 0.0914

Gnomad OTH exome AF: 0.0950

GnomAD4 exome AF: 0.0936 AC: 134950 AN: 1441262 Hom.: 6669 Cov.: 27 AF XY: 0.0950 AC XY: 68267 AN XY: 718308

Gnomad4 AFR exome AF: 0.0469

Gnomad4 AMR exome AF: 0.0530

Gnomad4 ASJ exome AF: 0.0841

Gnomad4 EAS exome AF: 0.175

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.0651

Gnomad4 NFE exome AF: 0.0926

Gnomad4 OTH exome AF: 0.0954

GnomAD4 genome AF: 0.0798 AC: 12140 AN: 152180 Hom.: 539 Cov.: 32 AF XY: 0.0796 AC XY: 5922 AN XY: 74388

Gnomad4 AFR AF: 0.0482

Gnomad4 AMR AF: 0.0730

Gnomad4 ASJ AF: 0.0851

Gnomad4 EAS AF: 0.182

Gnomad4 SAS AF: 0.134

Gnomad4 FIN AF: 0.0621

Gnomad4 NFE AF: 0.0917

Gnomad4 OTH AF: 0.0932

Alfa AF: 0.0906 Hom.: 1098

Bravo AF: 0.0773

Asia WGS AF: 0.154 AC: 533 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive Alport syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.73
Dann	Benign	0.50

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: rs2272205; hg19: chr2-227915924; COSMIC: COSV61631547;