2-227002830-G-GTCTT

Position:

• chr2-227002830-G-GTCTT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000092.5(COL4A4):​c.*4494_*4495insAAGA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 152,320 control chromosomes in the GnomAD database, including 42 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (42 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL4A4 NM_000092.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0330

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 -10 ACMG points.

• BP6: Variant 2-227002830-G-GTCTT is Benign according to our data. Variant chr2-227002830-G-GTCTT is described in ClinVar as [Likely_benign]. Clinvar id is 334640.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0148 (2248/152320) while in subpopulation AFR AF= 0.0516 (2145/41554). AF 95% confidence interval is 0.0498. There are 42 homozygotes in gnomad4. There are 1063 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 42 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A4	NM_000092.5	c.*4494_*4495insAAGA		3_prime_UTR_variant	48/48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5	c.*4494_*4495insAAGA		3_prime_UTR_variant	48/48	5	NM_000092.5	ENSP00000379866	P1

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2246 AN: 152202 Hom.: 42 Cov.: 33

Gnomad AFR AF: 0.0517

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0115

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 426 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 254

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0148 AC: 2248 AN: 152320 Hom.: 42 Cov.: 33 AF XY: 0.0143 AC XY: 1063 AN XY: 74490

Gnomad4 AFR AF: 0.0516

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.0112 Hom.: 3

Bravo AF: 0.0167

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alport syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs151077907; hg19: chr2-227867546;