2-227027145-T-C

Variant names:

• chr2-227027145-T-C
• rs1949807
• NM_000092.5:c.4081+757A>G

Variant summary

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

The NM_000092.5(COL4A4):​c.4081+757A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 151,286 control chromosomes in the GnomAD database, including 16,827 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 0.47 (16827 hom., cov: 28)
• Consequence: COL4A4 NM_000092.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.308
• Publications: 8 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=-0.99).
• 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.4081+757A>G		intron_variant	Intron 42 of 47	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.4081+757A>G		intron_variant	Intron 42 of 47	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.469 AC: 70856 AN: 151168 Hom.: 16793 Cov.: 28

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.435

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

GnomAD4 genome AF: 0.469 AC: 70935 AN: 151286 Hom.: 16827 Cov.: 28 AF XY: 0.470 AC XY: 34698 AN XY: 73866

African (AFR) AF: 0.534 AC: 21977 AN: 41128

American (AMR) AF: 0.471 AC: 7160 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1716 AN: 3460

East Asian (EAS) AF: 0.386 AC: 1980 AN: 5124

South Asian (SAS) AF: 0.545 AC: 2620 AN: 4804

European-Finnish (FIN) AF: 0.492 AC: 5139 AN: 10436

Middle Eastern (MID) AF: 0.404 AC: 118 AN: 292

European-Non Finnish (NFE) AF: 0.427 AC: 28960 AN: 67836

Other (OTH) AF: 0.430 AC: 902 AN: 2098

Alfa AF: 0.339 Hom.: 992

Bravo AF: 0.471

Asia WGS AF: 0.476 AC: 1659 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	5.1
DANN	Benign	0.49
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1949807; hg19: chr2-227891861;