rs648705

Variant names:

• chr13-110203806-A-C
• rs648705
• NM_001845.6:c.958-199T>G

Your query was ambiguous. Multiple possible variants found:

• chr13-110203806-A-C
• chr13-110203806-A-G
• chr13-110203806-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001845.6(COL4A1):​c.958-199T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 152,030 control chromosomes in the GnomAD database, including 25,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.57 (25982 hom., cov: 33)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.597
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 13-110203806-A-C is Benign according to our data. Variant chr13-110203806-A-C is described in ClinVar as Benign. ClinVar VariationId is 1293046.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.958-199T>G		intron_variant	Intron 17 of 51	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.958-199T>G		intron_variant	Intron 17 of 24		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.958-199T>G		intron_variant	Intron 17 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87164 AN: 151912 Hom.: 25986 Cov.: 33

Gnomad AFR AF: 0.413

Gnomad AMI AF: 0.879

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.698

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.699

Gnomad FIN AF: 0.609

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.619

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

GnomAD4 genome AF: 0.573 AC: 87174 AN: 152030 Hom.: 25982 Cov.: 33 AF XY: 0.575 AC XY: 42749 AN XY: 74314

African (AFR) AF: 0.412 AC: 17094 AN: 41460

American (AMR) AF: 0.543 AC: 8296 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.698 AC: 2422 AN: 3470

East Asian (EAS) AF: 0.762 AC: 3933 AN: 5160

South Asian (SAS) AF: 0.700 AC: 3374 AN: 4820

European-Finnish (FIN) AF: 0.609 AC: 6425 AN: 10550

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.638 AC: 43345 AN: 67974

Other (OTH) AF: 0.616 AC: 1300 AN: 2112

Alfa AF: 0.620 Hom.: 14359

Bravo AF: 0.562

Asia WGS AF: 0.684 AC: 2379 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 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	-0.86
CADD	Benign	1.6
DANN	Benign	0.49
PhyloP100		0.60
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: rs648705; hg19: chr13-110856153; COSMIC: COSV65421097; COSMIC: COSV65421097;