chr13-110172917-G-T

Variant names:

• chr13-110172917-G-T
• rs17517598
• NM_001845.6:c.3506-147C>A

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.3506-147C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 731,658 control chromosomes in the GnomAD database, including 8,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1424 hom., cov: 33)
  • Exomes 𝑓: 0.14 (7066 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.15
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 13-110172917-G-T is Benign according to our data. Variant chr13-110172917-G-T is described in ClinVar as Benign. ClinVar VariationId is 1251886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.3506-147C>A		intron_variant	Intron 40 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.3506-147C>A		intron_variant	Intron 40 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18146 AN: 152100 Hom.: 1425 Cov.: 33

Gnomad AFR AF: 0.0340

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.0969

GnomAD4 exome AF: 0.144 AC: 83484 AN: 579440 Hom.: 7066 AF XY: 0.145 AC XY: 45135 AN XY: 310604

African (AFR) AF: 0.0333 AC: 540 AN: 16198

American (AMR) AF: 0.111 AC: 3823 AN: 34586

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 2606 AN: 19148

East Asian (EAS) AF: 0.000273 AC: 9 AN: 32932

South Asian (SAS) AF: 0.135 AC: 8443 AN: 62346

European-Finnish (FIN) AF: 0.228 AC: 10736 AN: 47134

Middle Eastern (MID) AF: 0.0904 AC: 359 AN: 3972

European-Non Finnish (NFE) AF: 0.159 AC: 52745 AN: 332242

Other (OTH) AF: 0.137 AC: 4223 AN: 30882

GnomAD4 genome AF: 0.119 AC: 18141 AN: 152218 Hom.: 1424 Cov.: 33 AF XY: 0.123 AC XY: 9124 AN XY: 74410

African (AFR) AF: 0.0339 AC: 1410 AN: 41556

American (AMR) AF: 0.115 AC: 1758 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 502 AN: 3472

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5194

South Asian (SAS) AF: 0.123 AC: 592 AN: 4814

European-Finnish (FIN) AF: 0.241 AC: 2546 AN: 10570

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10961 AN: 67998

Other (OTH) AF: 0.0959 AC: 203 AN: 2116

Alfa AF: 0.140 Hom.: 1253

Bravo AF: 0.104

Asia WGS AF: 0.0380 AC: 137 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	-0.90
CADD	Benign	0.030
DANN	Benign	0.24
PhyloP100		-2.1
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: rs17517598; hg19: chr13-110825264;