rs683309

Variant names:

• chr13-110198423-T-C
• rs683309
• NM_001845.6:c.1285+44A>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.1285+44A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,610,784 control chromosomes in the GnomAD database, including 611,269 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (58353 hom., cov: 30)
  • Exomes 𝑓: 0.87 (552916 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.46
• Publications: 6 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=-0.99).
• BP6: Variant 13-110198423-T-C is Benign according to our data. Variant chr13-110198423-T-C is described in ClinVar as Benign. ClinVar VariationId is 1242809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.1285+44A>G		intron_variant	Intron 21 of 51	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.1285+44A>G		intron_variant	Intron 21 of 24		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.1285+44A>G		intron_variant	Intron 21 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.875 AC: 133054 AN: 151982 Hom.: 58299 Cov.: 30

Gnomad AFR AF: 0.858

Gnomad AMI AF: 0.773

Gnomad AMR AF: 0.892

Gnomad ASJ AF: 0.874

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.867

Gnomad FIN AF: 0.912

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.870

Gnomad OTH AF: 0.864

GnomAD2 exomes AF: 0.890 AC: 219742 AN: 246966 AF XY: 0.886

Gnomad AFR exome AF: 0.863

Gnomad AMR exome AF: 0.925

Gnomad ASJ exome AF: 0.890

Gnomad EAS exome AF: 0.997

Gnomad FIN exome AF: 0.905

Gnomad NFE exome AF: 0.870

Gnomad OTH exome AF: 0.885

GnomAD4 exome AF: 0.870 AC: 1269512 AN: 1458686 Hom.: 552916 Cov.: 36 AF XY: 0.869 AC XY: 630787 AN XY: 725638

African (AFR) AF: 0.856 AC: 28590 AN: 33400

American (AMR) AF: 0.923 AC: 41251 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.885 AC: 23106 AN: 26116

East Asian (EAS) AF: 0.983 AC: 39000 AN: 39690

South Asian (SAS) AF: 0.864 AC: 74437 AN: 86150

European-Finnish (FIN) AF: 0.901 AC: 47499 AN: 52708

Middle Eastern (MID) AF: 0.925 AC: 4279 AN: 4626

European-Non Finnish (NFE) AF: 0.863 AC: 958802 AN: 1111090

Other (OTH) AF: 0.873 AC: 52548 AN: 60216

GnomAD4 genome AF: 0.876 AC: 133167 AN: 152098 Hom.: 58353 Cov.: 30 AF XY: 0.880 AC XY: 65443 AN XY: 74366

African (AFR) AF: 0.859 AC: 35604 AN: 41472

American (AMR) AF: 0.893 AC: 13636 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.874 AC: 3033 AN: 3470

East Asian (EAS) AF: 0.991 AC: 5108 AN: 5154

South Asian (SAS) AF: 0.867 AC: 4172 AN: 4812

European-Finnish (FIN) AF: 0.912 AC: 9665 AN: 10598

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.870 AC: 59157 AN: 67996

Other (OTH) AF: 0.864 AC: 1825 AN: 2112

Alfa AF: 0.874 Hom.: 74506

Bravo AF: 0.874

Asia WGS AF: 0.920 AC: 3197 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	-0.99
CADD	Benign	0.20
DANN	Benign	0.38
PhyloP100		-1.5
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: rs683309; hg19: chr13-110850770; COSMIC: COSV65432582;