2-227092767-G-C

Variant names:

• chr2-227092767-G-C
• rs4389330
• NM_000092.5:c.1369+1358C>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.1369+1358C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.688 in 152,054 control chromosomes in the GnomAD database, including 37,066 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 0.69 (37066 hom., cov: 32)
• Consequence: COL4A4 NM_000092.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.640
• Publications: 2 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.1369+1358C>G		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+1358C>G		intron_variant	Intron 20 of 47	5	NM_000092.5	ENSP00000379866.3

Frequencies

GnomAD3 genomes AF: 0.688 AC: 104574 AN: 151936 Hom.: 37017 Cov.: 32

Gnomad AFR AF: 0.852

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.701

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.770

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.651

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.662

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

GnomAD4 genome AF: 0.688 AC: 104682 AN: 152054 Hom.: 37066 Cov.: 32 AF XY: 0.685 AC XY: 50908 AN XY: 74324

African (AFR) AF: 0.852 AC: 35367 AN: 41500

American (AMR) AF: 0.701 AC: 10713 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2162 AN: 3466

East Asian (EAS) AF: 0.501 AC: 2592 AN: 5178

South Asian (SAS) AF: 0.770 AC: 3707 AN: 4812

European-Finnish (FIN) AF: 0.557 AC: 5869 AN: 10534

Middle Eastern (MID) AF: 0.652 AC: 189 AN: 290

European-Non Finnish (NFE) AF: 0.617 AC: 41962 AN: 67968

Other (OTH) AF: 0.664 AC: 1400 AN: 2108

Alfa AF: 0.512 Hom.: 1287

Bravo AF: 0.702

Asia WGS AF: 0.661 AC: 2295 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.34
DANN	Benign	0.29
PhyloP100		-0.64
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: rs4389330; hg19: chr2-227957483;