rs7558081

Variant names:

• chr2-227093753-C-T
• rs7558081
• NM_000092.5:c.1369+372G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000092.5(COL4A4):​c.1369+372G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 151,904 control chromosomes in the GnomAD database, including 19,646 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.51 (19646 hom., cov: 32)
• Consequence: COL4A4 NM_000092.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.627
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.1369+372G>A		intron_variant	Intron 20 of 47	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.1369+372G>A		intron_variant	Intron 20 of 47	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.507 AC: 77029 AN: 151788 Hom.: 19624 Cov.: 32

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.498

Gnomad EAS AF: 0.547

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.494

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.508 AC: 77100 AN: 151904 Hom.: 19646 Cov.: 32 AF XY: 0.511 AC XY: 37902 AN XY: 74234

African (AFR) AF: 0.475 AC: 19666 AN: 41434

American (AMR) AF: 0.598 AC: 9131 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.498 AC: 1727 AN: 3470

East Asian (EAS) AF: 0.547 AC: 2816 AN: 5148

South Asian (SAS) AF: 0.560 AC: 2693 AN: 4808

European-Finnish (FIN) AF: 0.532 AC: 5598 AN: 10516

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.498 AC: 33836 AN: 67946

Other (OTH) AF: 0.495 AC: 1045 AN: 2112

Alfa AF: 0.500 Hom.: 31601

Bravo AF: 0.509

Asia WGS AF: 0.583 AC: 2025 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.2
DANN	Benign	0.95
PhyloP100		-0.63
Mutation Taster		=100/0	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: rs7558081; hg19: chr2-227958469;