rs9521649

Variant names:

• chr13-110209956-G-A
• rs9521649
• NM_001845.6:c.615+24C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-110209956-G-A
• chr13-110209956-G-C

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.615+24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,611,612 control chromosomes in the GnomAD database, including 53,456 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4616 hom., cov: 32)
  • Exomes 𝑓: 0.25 (48840 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.252
• Publications: 9 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 13-110209956-G-A is Benign according to our data. Variant chr13-110209956-G-A is described in ClinVar as Benign. ClinVar VariationId is 1227525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.615+24C>T		intron_variant	Intron 10 of 51	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.615+24C>T		intron_variant	Intron 10 of 24		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.615+24C>T		intron_variant	Intron 10 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35826 AN: 151916 Hom.: 4613 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.0468

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.211

GnomAD2 exomes AF: 0.247 AC: 61989 AN: 251132 AF XY: 0.245

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.0407

Gnomad FIN exome AF: 0.315

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.253 AC: 368965 AN: 1459578 Hom.: 48840 Cov.: 33 AF XY: 0.253 AC XY: 183404 AN XY: 726262

African (AFR) AF: 0.166 AC: 5568 AN: 33450

American (AMR) AF: 0.327 AC: 14640 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 6243 AN: 26122

East Asian (EAS) AF: 0.0322 AC: 1279 AN: 39690

South Asian (SAS) AF: 0.229 AC: 19770 AN: 86232

European-Finnish (FIN) AF: 0.313 AC: 16705 AN: 53388

Middle Eastern (MID) AF: 0.250 AC: 1440 AN: 5766

European-Non Finnish (NFE) AF: 0.260 AC: 289012 AN: 1109874

Other (OTH) AF: 0.237 AC: 14308 AN: 60342

GnomAD4 genome AF: 0.236 AC: 35850 AN: 152034 Hom.: 4616 Cov.: 32 AF XY: 0.239 AC XY: 17762 AN XY: 74304

African (AFR) AF: 0.168 AC: 6984 AN: 41468

American (AMR) AF: 0.310 AC: 4741 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 847 AN: 3466

East Asian (EAS) AF: 0.0465 AC: 240 AN: 5162

South Asian (SAS) AF: 0.213 AC: 1023 AN: 4808

European-Finnish (FIN) AF: 0.322 AC: 3399 AN: 10568

Middle Eastern (MID) AF: 0.247 AC: 72 AN: 292

European-Non Finnish (NFE) AF: 0.265 AC: 18045 AN: 67974

Other (OTH) AF: 0.209 AC: 440 AN: 2108

Alfa AF: 0.252 Hom.: 2266

Bravo AF: 0.228

Asia WGS AF: 0.125 AC: 435 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	0.18
DANN	Benign	0.47
PhyloP100		-0.25
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: rs9521649; hg19: chr13-110862303; COSMIC: COSV65423082;