rs2305081

Variant names:

• chr13-110177743-G-A
• rs2305081
• NM_001845.6:c.2716+99C>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.2716+99C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,267,340 control chromosomes in the GnomAD database, including 14,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1551 hom., cov: 32)
  • Exomes 𝑓: 0.15 (13272 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.23
• Publications: 4 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=-0.84).
• BP6: Variant 13-110177743-G-A is Benign according to our data. Variant chr13-110177743-G-A is described in ClinVar as [Benign]. Clinvar id is 1225740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.2716+99C>T		intron_variant	Intron 33 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.2716+99C>T		intron_variant	Intron 33 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19871 AN: 151768 Hom.: 1547 Cov.: 32

Gnomad AFR AF: 0.0533

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.136

GnomAD4 exome AF: 0.151 AC: 168034 AN: 1115454 Hom.: 13272 AF XY: 0.150 AC XY: 85809 AN XY: 570436

African (AFR) AF: 0.0483 AC: 1300 AN: 26936

American (AMR) AF: 0.191 AC: 8094 AN: 42418

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 4522 AN: 23760

East Asian (EAS) AF: 0.0857 AC: 3224 AN: 37626

South Asian (SAS) AF: 0.141 AC: 11021 AN: 78314

European-Finnish (FIN) AF: 0.139 AC: 6725 AN: 48466

Middle Eastern (MID) AF: 0.159 AC: 564 AN: 3546

European-Non Finnish (NFE) AF: 0.156 AC: 125363 AN: 805300

Other (OTH) AF: 0.147 AC: 7221 AN: 49088

GnomAD4 genome AF: 0.131 AC: 19881 AN: 151886 Hom.: 1551 Cov.: 32 AF XY: 0.131 AC XY: 9742 AN XY: 74216

African (AFR) AF: 0.0532 AC: 2205 AN: 41458

American (AMR) AF: 0.166 AC: 2528 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 696 AN: 3466

East Asian (EAS) AF: 0.125 AC: 642 AN: 5118

South Asian (SAS) AF: 0.146 AC: 700 AN: 4806

European-Finnish (FIN) AF: 0.130 AC: 1365 AN: 10506

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11078 AN: 67954

Other (OTH) AF: 0.134 AC: 284 AN: 2116

Alfa AF: 0.154 Hom.: 3356

Bravo AF: 0.130

Asia WGS AF: 0.111 AC: 386 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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	-0.84
CADD	Benign	0.91
DANN	Benign	0.53
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2305081; hg19: chr13-110830090;