rs75270666

Variant names:

• chr13-110242853-G-A
• rs75270666
• NM_001845.6:c.85-119C>T

Variant summary

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

The NM_001845.6(COL4A1):​c.85-119C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00968 in 1,100,190 control chromosomes in the GnomAD database, including 480 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 0.012 (78 hom., cov: 33)
  • Exomes 𝑓: 0.0092 (402 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.525
• Publications: 1 publications found

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]

COL4A1 Gene-Disease associations (from GenCC):

• brain small vessel disease 1 with or without ocular anomalies

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, PanelApp Australia, Orphanet, Genomics England PanelApp
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
• microangiopathy and leukoencephalopathy, pontine, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• familial porencephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pontine autosomal dominant microangiopathy with leukoencephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinal arterial tortuosity

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.85-119C>T		intron_variant	Intron 1 of 51	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.85-119C>T		intron_variant	Intron 1 of 24		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.85-119C>T		intron_variant	Intron 1 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1898 AN: 152166 Hom.: 78 Cov.: 33

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0799

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0426

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00956

GnomAD4 exome AF: 0.00923 AC: 8751 AN: 947906 Hom.: 402 AF XY: 0.00798 AC XY: 3937 AN XY: 493516

African (AFR) AF: 0.00193 AC: 45 AN: 23292

American (AMR) AF: 0.121 AC: 5248 AN: 43244

Ashkenazi Jewish (ASJ) AF: 0.00495 AC: 113 AN: 22828

East Asian (EAS) AF: 0.0443 AC: 1652 AN: 37294

South Asian (SAS) AF: 0.00134 AC: 101 AN: 75420

European-Finnish (FIN) AF: 0.0227 AC: 945 AN: 41556

Middle Eastern (MID) AF: 0.000838 AC: 4 AN: 4774

European-Non Finnish (NFE) AF: 0.000415 AC: 272 AN: 655638

Other (OTH) AF: 0.00846 AC: 371 AN: 43860

GnomAD4 genome AF: 0.0125 AC: 1902 AN: 152284 Hom.: 78 Cov.: 33 AF XY: 0.0153 AC XY: 1140 AN XY: 74450

African (AFR) AF: 0.00188 AC: 78 AN: 41572

American (AMR) AF: 0.0801 AC: 1224 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.0427 AC: 221 AN: 5176

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.0283 AC: 300 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68032

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00601 Hom.: 5

Bravo AF: 0.0170

Asia WGS AF: 0.0210 AC: 72 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.47
PhyloP100		-0.53
PromoterAI		0.0040	Neutral
Mutation Taster		=100/0	polymorphism

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: rs75270666; hg19: chr13-110895200; COSMIC: COSV65433493;