2-227084010-A-T

Variant names:

• chr2-227084010-A-T
• rs3923084
• NM_000092.5:c.1624-1823T>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.1624-1823T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 152,216 control chromosomes in the GnomAD database, including 1,075 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 0.11 (1075 hom., cov: 32)
• Consequence: COL4A4 NM_000092.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.33
• Publications: 5 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.1624-1823T>A		intron_variant	Intron 22 of 47	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.1624-1823T>A		intron_variant	Intron 22 of 47	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16956 AN: 152098 Hom.: 1063 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0861

Gnomad ASJ AF: 0.0726

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0607

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0842

Gnomad OTH AF: 0.115

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

GnomAD4 genome AF: 0.112 AC: 17004 AN: 152216 Hom.: 1075 Cov.: 32 AF XY: 0.111 AC XY: 8262 AN XY: 74428

African (AFR) AF: 0.174 AC: 7221 AN: 41508

American (AMR) AF: 0.0859 AC: 1314 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0726 AC: 252 AN: 3472

East Asian (EAS) AF: 0.188 AC: 969 AN: 5164

South Asian (SAS) AF: 0.119 AC: 572 AN: 4824

European-Finnish (FIN) AF: 0.0607 AC: 645 AN: 10622

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.0842 AC: 5726 AN: 68008

Other (OTH) AF: 0.119 AC: 252 AN: 2114

Alfa AF: 0.0262 Hom.: 16

Bravo AF: 0.115

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.0010
DANN	Benign	0.30
PhyloP100		-2.3
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: rs3923084; hg19: chr2-227948726;