rs1975514

Variant names:

• chr13-110176544-T-C
• rs1975514
• NM_001845.6:c.2969-31A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-110176544-T-C
• chr13-110176544-T-G

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.2969-31A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 1,596,810 control chromosomes in the GnomAD database, including 104,856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.34 (8872 hom., cov: 32)
  • Exomes 𝑓: 0.36 (95984 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.279
• Publications: 12 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-110176544-T-C is Benign according to our data. Variant chr13-110176544-T-C is described in ClinVar as Benign. ClinVar VariationId is 1293324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.2969-31A>G		intron_variant	Intron 35 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.2969-31A>G		intron_variant	Intron 35 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51665 AN: 151916 Hom.: 8859 Cov.: 32

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.354

GnomAD2 exomes AF: 0.356 AC: 89231 AN: 250612 AF XY: 0.357

Gnomad AFR exome AF: 0.279

Gnomad AMR exome AF: 0.396

Gnomad ASJ exome AF: 0.316

Gnomad EAS exome AF: 0.302

Gnomad FIN exome AF: 0.351

Gnomad NFE exome AF: 0.365

Gnomad OTH exome AF: 0.352

GnomAD4 exome AF: 0.362 AC: 523171 AN: 1444776 Hom.: 95984 Cov.: 28 AF XY: 0.362 AC XY: 260885 AN XY: 719874

African (AFR) AF: 0.269 AC: 8923 AN: 33166

American (AMR) AF: 0.393 AC: 17549 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 8283 AN: 26010

East Asian (EAS) AF: 0.268 AC: 10614 AN: 39632

South Asian (SAS) AF: 0.365 AC: 31334 AN: 85896

European-Finnish (FIN) AF: 0.353 AC: 18828 AN: 53370

Middle Eastern (MID) AF: 0.264 AC: 1516 AN: 5736

European-Non Finnish (NFE) AF: 0.369 AC: 404915 AN: 1096474

Other (OTH) AF: 0.355 AC: 21209 AN: 59822

GnomAD4 genome AF: 0.340 AC: 51718 AN: 152034 Hom.: 8872 Cov.: 32 AF XY: 0.340 AC XY: 25290 AN XY: 74314

African (AFR) AF: 0.277 AC: 11498 AN: 41460

American (AMR) AF: 0.362 AC: 5539 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1182 AN: 3472

East Asian (EAS) AF: 0.302 AC: 1554 AN: 5150

South Asian (SAS) AF: 0.364 AC: 1753 AN: 4820

European-Finnish (FIN) AF: 0.349 AC: 3693 AN: 10576

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.370 AC: 25140 AN: 67964

Other (OTH) AF: 0.359 AC: 756 AN: 2106

Alfa AF: 0.281 Hom.: 1572

Bravo AF: 0.338

Asia WGS AF: 0.362 AC: 1256 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.61
DANN	Benign	0.43
PhyloP100		0.28
BranchPoint Hunter		1.0
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: rs1975514; hg19: chr13-110828891; COSMIC: COSV65430826;