rs10492497

Variant names:

• chr13-110179519-T-C
• rs10492497
• NM_001845.6:c.2194-98A>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.2194-98A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0752 in 1,537,726 control chromosomes in the GnomAD database, including 4,688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (437 hom., cov: 33)
  • Exomes 𝑓: 0.075 (4251 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.40
• Publications: 10 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 13-110179519-T-C is Benign according to our data. Variant chr13-110179519-T-C is described in ClinVar as Benign. ClinVar VariationId is 1293322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.2194-98A>G		intron_variant	Intron 29 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.2194-98A>G		intron_variant	Intron 29 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.0759 AC: 11558 AN: 152180 Hom.: 437 Cov.: 33

Gnomad AFR AF: 0.0761

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0871

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0646

Gnomad FIN AF: 0.0924

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0716

Gnomad OTH AF: 0.0784

GnomAD4 exome AF: 0.0752 AC: 104134 AN: 1385428 Hom.: 4251 AF XY: 0.0744 AC XY: 51587 AN XY: 693370

African (AFR) AF: 0.0758 AC: 2418 AN: 31906

American (AMR) AF: 0.119 AC: 5242 AN: 43998

Ashkenazi Jewish (ASJ) AF: 0.0169 AC: 431 AN: 25546

East Asian (EAS) AF: 0.138 AC: 5395 AN: 39236

South Asian (SAS) AF: 0.0673 AC: 5665 AN: 84134

European-Finnish (FIN) AF: 0.0878 AC: 4538 AN: 51674

Middle Eastern (MID) AF: 0.0220 AC: 124 AN: 5648

European-Non Finnish (NFE) AF: 0.0731 AC: 76390 AN: 1045374

Other (OTH) AF: 0.0679 AC: 3931 AN: 57912

GnomAD4 genome AF: 0.0760 AC: 11570 AN: 152298 Hom.: 437 Cov.: 33 AF XY: 0.0777 AC XY: 5783 AN XY: 74466

African (AFR) AF: 0.0762 AC: 3166 AN: 41564

American (AMR) AF: 0.0870 AC: 1331 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3472

East Asian (EAS) AF: 0.121 AC: 625 AN: 5184

South Asian (SAS) AF: 0.0644 AC: 311 AN: 4826

European-Finnish (FIN) AF: 0.0924 AC: 981 AN: 10616

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0717 AC: 4874 AN: 68018

Other (OTH) AF: 0.0781 AC: 165 AN: 2114

Alfa AF: 0.0712 Hom.: 781

Bravo AF: 0.0779

Asia WGS AF: 0.0970 AC: 336 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 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	-0.89
CADD	Benign	0.21
DANN	Benign	0.29
PhyloP100		-2.4
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: rs10492497; hg19: chr13-110831866; COSMIC: COSV65430829;