13-110186299-A-G

Variant names:

• chr13-110186299-A-G
• rs565470
• NM_001845.6:c.1897+86T>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.1897+86T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,551,680 control chromosomes in the GnomAD database, including 355,746 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34723 hom., cov: 33)
  • Exomes 𝑓: 0.68 (321023 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.531
• Publications: 11 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=-0.91).
• BP6: Variant 13-110186299-A-G is Benign according to our data. Variant chr13-110186299-A-G is described in ClinVar as Benign. ClinVar VariationId is 1249954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.1897+86T>C		intron_variant	Intron 26 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.1897+86T>C		intron_variant	Intron 26 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.674 AC: 102534 AN: 152016 Hom.: 34681 Cov.: 33

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.612

Gnomad EAS AF: 0.530

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.733

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.640

GnomAD4 exome AF: 0.675 AC: 945079 AN: 1399544 Hom.: 321023 AF XY: 0.673 AC XY: 470613 AN XY: 699264

African (AFR) AF: 0.668 AC: 21567 AN: 32292

American (AMR) AF: 0.754 AC: 33610 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 15043 AN: 25706

East Asian (EAS) AF: 0.519 AC: 20430 AN: 39330

South Asian (SAS) AF: 0.621 AC: 52268 AN: 84196

European-Finnish (FIN) AF: 0.733 AC: 38268 AN: 52182

Middle Eastern (MID) AF: 0.528 AC: 2135 AN: 4046

European-Non Finnish (NFE) AF: 0.683 AC: 723355 AN: 1059038

Other (OTH) AF: 0.660 AC: 38403 AN: 58190

GnomAD4 genome AF: 0.675 AC: 102641 AN: 152136 Hom.: 34723 Cov.: 33 AF XY: 0.676 AC XY: 50221 AN XY: 74340

African (AFR) AF: 0.665 AC: 27617 AN: 41504

American (AMR) AF: 0.705 AC: 10780 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 2122 AN: 3470

East Asian (EAS) AF: 0.530 AC: 2728 AN: 5146

South Asian (SAS) AF: 0.604 AC: 2912 AN: 4822

European-Finnish (FIN) AF: 0.733 AC: 7768 AN: 10598

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.684 AC: 46530 AN: 67986

Other (OTH) AF: 0.642 AC: 1355 AN: 2110

Alfa AF: 0.673 Hom.: 61830

Bravo AF: 0.672

Asia WGS AF: 0.575 AC: 2002 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	-0.91
CADD	Benign	0.87
DANN	Benign	0.22
PhyloP100		-0.53
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: rs565470; hg19: chr13-110838646; COSMIC: COSV65433787; COSMIC: COSV65433787;