rs652572

Variant names:

• chr13-110167110-A-G
• rs652572
• NM_001845.6:c.3949+48T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-110167110-A-G
• chr13-110167110-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001845.6(COL4A1):​c.3949+48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 1,504,160 control chromosomes in the GnomAD database, including 314,793 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27238 hom., cov: 31)
  • Exomes 𝑓: 0.65 (287555 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0210
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 13-110167110-A-G is Benign according to our data. Variant chr13-110167110-A-G is described in ClinVar as Benign. ClinVar VariationId is 1269926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.3949+48T>C		intron_variant	Intron 44 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.3949+48T>C		intron_variant	Intron 44 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89047 AN: 151432 Hom.: 27237 Cov.: 31

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.660

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.654

Gnomad SAS AF: 0.681

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.606

Gnomad NFE AF: 0.655

Gnomad OTH AF: 0.586

GnomAD2 exomes AF: 0.651 AC: 163568 AN: 251176 AF XY: 0.653

Gnomad AFR exome AF: 0.393

Gnomad AMR exome AF: 0.715

Gnomad ASJ exome AF: 0.599

Gnomad EAS exome AF: 0.652

Gnomad FIN exome AF: 0.734

Gnomad NFE exome AF: 0.657

Gnomad OTH exome AF: 0.633

GnomAD4 exome AF: 0.649 AC: 878332 AN: 1352608 Hom.: 287555 Cov.: 21 AF XY: 0.650 AC XY: 441522 AN XY: 679188

African (AFR) AF: 0.385 AC: 12118 AN: 31436

American (AMR) AF: 0.710 AC: 31624 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.600 AC: 15287 AN: 25468

East Asian (EAS) AF: 0.649 AC: 25426 AN: 39174

South Asian (SAS) AF: 0.659 AC: 55411 AN: 84020

European-Finnish (FIN) AF: 0.730 AC: 38889 AN: 53286

Middle Eastern (MID) AF: 0.576 AC: 3066 AN: 5322

European-Non Finnish (NFE) AF: 0.652 AC: 660042 AN: 1012550

Other (OTH) AF: 0.642 AC: 36469 AN: 56786

GnomAD4 genome AF: 0.588 AC: 89085 AN: 151552 Hom.: 27238 Cov.: 31 AF XY: 0.595 AC XY: 44049 AN XY: 74078

African (AFR) AF: 0.400 AC: 16538 AN: 41338

American (AMR) AF: 0.661 AC: 10070 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 2065 AN: 3468

East Asian (EAS) AF: 0.654 AC: 3340 AN: 5110

South Asian (SAS) AF: 0.679 AC: 3263 AN: 4804

European-Finnish (FIN) AF: 0.723 AC: 7590 AN: 10496

Middle Eastern (MID) AF: 0.603 AC: 175 AN: 290

European-Non Finnish (NFE) AF: 0.655 AC: 44387 AN: 67792

Other (OTH) AF: 0.590 AC: 1247 AN: 2112

Alfa AF: 0.591 Hom.: 8460

Bravo AF: 0.577

Asia WGS AF: 0.682 AC: 2374 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.9
DANN	Benign	0.28
PhyloP100		-0.021
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs652572; hg19: chr13-110819457;