rs2131939

Variant names:

• chr13-110179490-G-A
• rs2131939
• NM_001845.6:c.2194-69C>T

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.2194-69C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,605,950 control chromosomes in the GnomAD database, including 13,455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (888 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12567 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.43
• Publications: 8 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=-0.93).
• BP6: Variant 13-110179490-G-A is Benign according to our data. Variant chr13-110179490-G-A is described in ClinVar as [Benign]. Clinvar id is 1293381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.2194-69C>T		intron_variant	Intron 29 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.2194-69C>T		intron_variant	Intron 29 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.0949 AC: 14441 AN: 152116 Hom.: 888 Cov.: 33

Gnomad AFR AF: 0.0279

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.0961

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.105

GnomAD4 exome AF: 0.127 AC: 184849 AN: 1453716 Hom.: 12567 AF XY: 0.129 AC XY: 93328 AN XY: 723824

African (AFR) AF: 0.0235 AC: 782 AN: 33334

American (AMR) AF: 0.0722 AC: 3225 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2889 AN: 26078

East Asian (EAS) AF: 0.00767 AC: 304 AN: 39644

South Asian (SAS) AF: 0.154 AC: 13246 AN: 86078

European-Finnish (FIN) AF: 0.127 AC: 6679 AN: 52654

Middle Eastern (MID) AF: 0.0718 AC: 413 AN: 5756

European-Non Finnish (NFE) AF: 0.136 AC: 150037 AN: 1105398

Other (OTH) AF: 0.121 AC: 7274 AN: 60106

GnomAD4 genome AF: 0.0948 AC: 14437 AN: 152234 Hom.: 888 Cov.: 33 AF XY: 0.0942 AC XY: 7010 AN XY: 74434

African (AFR) AF: 0.0279 AC: 1157 AN: 41540

American (AMR) AF: 0.0959 AC: 1467 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 415 AN: 3470

East Asian (EAS) AF: 0.00463 AC: 24 AN: 5184

South Asian (SAS) AF: 0.150 AC: 724 AN: 4824

European-Finnish (FIN) AF: 0.125 AC: 1328 AN: 10592

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.131 AC: 8937 AN: 68014

Other (OTH) AF: 0.105 AC: 223 AN: 2116

Alfa AF: 0.114 Hom.: 2247

Bravo AF: 0.0874

Asia WGS AF: 0.0720 AC: 249 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

- -

Jul 07, 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	-0.93
CADD	Benign	0.060
DANN	Benign	0.64
PhyloP100		-1.4
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: rs2131939; hg19: chr13-110831837;