rs685884

Variant names:

• chr13-110192967-G-A
• rs685884
• NM_001845.6:c.1382-54C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-110192967-G-A
• chr13-110192967-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.1382-54C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.73 in 1,520,384 control chromosomes in the GnomAD database, including 406,547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39333 hom., cov: 33)
  • Exomes 𝑓: 0.73 (367214 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.124
• 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=-0.87).
• BP6: Variant 13-110192967-G-A is Benign according to our data. Variant chr13-110192967-G-A is described in ClinVar as Benign. ClinVar VariationId is 1243583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.1382-54C>T		intron_variant	Intron 22 of 51	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.1382-54C>T		intron_variant	Intron 22 of 24		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.1382-54C>T		intron_variant	Intron 22 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.717 AC: 109031 AN: 152038 Hom.: 39305 Cov.: 33

Gnomad AFR AF: 0.695

Gnomad AMI AF: 0.933

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.724

Gnomad EAS AF: 0.928

Gnomad SAS AF: 0.795

Gnomad FIN AF: 0.671

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.723

Gnomad OTH AF: 0.753

GnomAD4 exome AF: 0.731 AC: 1000270 AN: 1368228 Hom.: 367214 AF XY: 0.733 AC XY: 503035 AN XY: 686446

African (AFR) AF: 0.688 AC: 21795 AN: 31662

American (AMR) AF: 0.653 AC: 29019 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.726 AC: 18516 AN: 25516

East Asian (EAS) AF: 0.943 AC: 37017 AN: 39264

South Asian (SAS) AF: 0.776 AC: 65416 AN: 84294

European-Finnish (FIN) AF: 0.674 AC: 35904 AN: 53238

Middle Eastern (MID) AF: 0.741 AC: 4142 AN: 5588

European-Non Finnish (NFE) AF: 0.727 AC: 746060 AN: 1026902

Other (OTH) AF: 0.740 AC: 42401 AN: 57306

GnomAD4 genome AF: 0.717 AC: 109113 AN: 152156 Hom.: 39333 Cov.: 33 AF XY: 0.717 AC XY: 53360 AN XY: 74382

African (AFR) AF: 0.695 AC: 28854 AN: 41502

American (AMR) AF: 0.668 AC: 10219 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.724 AC: 2511 AN: 3468

East Asian (EAS) AF: 0.928 AC: 4799 AN: 5172

South Asian (SAS) AF: 0.795 AC: 3836 AN: 4824

European-Finnish (FIN) AF: 0.671 AC: 7093 AN: 10574

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.723 AC: 49143 AN: 68006

Other (OTH) AF: 0.755 AC: 1595 AN: 2112

Alfa AF: 0.724 Hom.: 65744

Bravo AF: 0.718

Asia WGS AF: 0.863 AC: 2995 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	-0.87
CADD	Benign	1.2
DANN	Benign	0.37
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs685884; hg19: chr13-110845314;