13-110149715-A-AAT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001845.6(COL4A1):c.*647_*648insAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000508 in 151,694 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (0 hom.)
• Consequence: COL4A1 NM_001845.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 3.41

Genes affected

COL4A1 (HGNC:2202): (collagen type IV alpha 1 chain) This gene encodes a type IV collagen alpha protein. Type IV collagen proteins are integral components of basement membranes. This gene shares a bidirectional promoter with a paralogous gene on the opposite strand. The protein consists of an amino-terminal 7S domain, a triple-helix forming collagenous domain, and a carboxy-terminal non-collagenous domain. It functions as part of a heterotrimer and interacts with other extracellular matrix components such as perlecans, proteoglycans, and laminins. In addition, proteolytic cleavage of the non-collagenous carboxy-terminal domain results in a biologically active fragment known as arresten, which has anti-angiogenic and tumor suppressor properties. Mutations in this gene cause porencephaly, cerebrovascular disease, and renal and muscular defects. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000502 (76/151256) while in subpopulation EAS AF= 0.00116 (6/5166). AF 95% confidence interval is 0.000506. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.*647_*648insAT		3_prime_UTR_variant	52/52	ENST00000375820.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.*647_*648insAT		3_prime_UTR_variant	52/52	1	NM_001845.6	P1
COL4A1	ENST00000650424.1	c.*647_*648insAT		3_prime_UTR_variant	10/10
COL4A1	ENST00000649720.1	n.1825_1826insAT		non_coding_transcript_exon_variant	7/7

Frequencies

GnomAD3 genomes AF: 0.000503 AC: 76 AN: 151150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00550

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00228 AC: 1 AN: 438 Hom.: 0 Cov.: 0 AF XY: 0.00373 AC XY: 1 AN XY: 268

Gnomad4 FIN exome AF: 0.00239

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000502 AC: 76 AN: 151256 Hom.: 0 Cov.: 33 AF XY: 0.000785 AC XY: 58 AN XY: 73894

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000263

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00550

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000185

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

Brain small vessel disease 1 with or without ocular anomalies Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Porencephalic cyst Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome Uncertain:1

Uncertain significance, 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: rs886049952; hg19: chr13-110802062;