rs681884

Variant names:

• chr13-110152715-G-A
• rs681884
• NM_001845.6:c.4756-209C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-110152715-G-A
• chr13-110152715-G-C
• chr13-110152715-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001845.6(COL4A1):​c.4756-209C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 152,234 control chromosomes in the GnomAD database, including 45,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.77 (45839 hom., cov: 34)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.01
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 13-110152715-G-A is Benign according to our data. Variant chr13-110152715-G-A is described in ClinVar as Benign. ClinVar VariationId is 1269380.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001845.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	NM_001845.6	MANE Select	c.4756-209C>T		intron	N/A	NP_001836.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.4756-209C>T		intron	N/A	ENSP00000364979.4
	COL4A1	ENST00000650424.2		c.4756-209C>T		intron	N/A	ENSP00000497477.2
	COL4A1	ENST00000615732.3	TSL:5	c.4564-209C>T		intron	N/A	ENSP00000478222.3

Frequencies

GnomAD3 genomes AF: 0.768 AC: 116830 AN: 152116 Hom.: 45775 Cov.: 34

Gnomad AFR AF: 0.910

Gnomad AMI AF: 0.656

Gnomad AMR AF: 0.793

Gnomad ASJ AF: 0.776

Gnomad EAS AF: 0.987

Gnomad SAS AF: 0.761

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.809

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.788

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.768 AC: 116955 AN: 152234 Hom.: 45839 Cov.: 34 AF XY: 0.770 AC XY: 57275 AN XY: 74408

African (AFR) AF: 0.910 AC: 37845 AN: 41572

American (AMR) AF: 0.793 AC: 12134 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.776 AC: 2696 AN: 3472

East Asian (EAS) AF: 0.987 AC: 5091 AN: 5156

South Asian (SAS) AF: 0.760 AC: 3670 AN: 4826

European-Finnish (FIN) AF: 0.660 AC: 6987 AN: 10592

Middle Eastern (MID) AF: 0.812 AC: 237 AN: 292

European-Non Finnish (NFE) AF: 0.677 AC: 46027 AN: 67998

Other (OTH) AF: 0.790 AC: 1670 AN: 2114

Alfa AF: 0.726 Hom.: 8982

Bravo AF: 0.787

Asia WGS AF: 0.900 AC: 3126 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.020
DANN	Benign	0.46
PhyloP100		-1.0
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: rs681884; hg19: chr13-110805062;