13-110155429-C-T

Variant names:

• chr13-110155429-C-T
• rs617111
• NM_001845.6:c.4641-32G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000375820.10(COL4A1):​c.4641-32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,554,910 control chromosomes in the GnomAD database, including 2,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (1394 hom., cov: 33)
  • Exomes 𝑓: 0.015 (1195 hom.)
• Consequence: COL4A1 ENST00000375820.10 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.89
• Publications: 2 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=-0.88).
• BP6: Variant 13-110155429-C-T is Benign according to our data. Variant chr13-110155429-C-T is described in ClinVar as Benign. ClinVar VariationId is 1298231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000375820.10. 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.4641-32G>A		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.4641-32G>A		intron	N/A	ENSP00000364979.4
	COL4A1	ENST00000650424.2		c.4641-32G>A		intron	N/A	ENSP00000497477.2
	COL4A1	ENST00000615732.3	TSL:5	c.4449-32G>A		intron	N/A	ENSP00000478222.3

Frequencies

GnomAD3 genomes AF: 0.0778 AC: 11835 AN: 152148 Hom.: 1387 Cov.: 33

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.0306

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00934

Gnomad OTH AF: 0.0651

GnomAD2 exomes AF: 0.0257 AC: 6151 AN: 239142 AF XY: 0.0212

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.0213

Gnomad ASJ exome AF: 0.0376

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00215

Gnomad NFE exome AF: 0.00911

Gnomad OTH exome AF: 0.0201

GnomAD4 exome AF: 0.0150 AC: 21047 AN: 1402644 Hom.: 1195 Cov.: 23 AF XY: 0.0140 AC XY: 9815 AN XY: 700540

African (AFR) AF: 0.258 AC: 8328 AN: 32238

American (AMR) AF: 0.0222 AC: 977 AN: 43990

Ashkenazi Jewish (ASJ) AF: 0.0348 AC: 893 AN: 25684

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39196

South Asian (SAS) AF: 0.00466 AC: 394 AN: 84486

European-Finnish (FIN) AF: 0.00166 AC: 88 AN: 52936

Middle Eastern (MID) AF: 0.0461 AC: 257 AN: 5572

European-Non Finnish (NFE) AF: 0.00812 AC: 8609 AN: 1060274

Other (OTH) AF: 0.0257 AC: 1500 AN: 58268

GnomAD4 genome AF: 0.0780 AC: 11878 AN: 152266 Hom.: 1394 Cov.: 33 AF XY: 0.0741 AC XY: 5516 AN XY: 74466

African (AFR) AF: 0.252 AC: 10479 AN: 41532

American (AMR) AF: 0.0315 AC: 482 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0306 AC: 106 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00434 AC: 21 AN: 4834

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10628

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00934 AC: 635 AN: 68014

Other (OTH) AF: 0.0644 AC: 136 AN: 2112

Alfa AF: 0.0341 Hom.: 190

Bravo AF: 0.0876

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.013
DANN	Benign	0.38
PhyloP100		-1.9
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: rs617111; hg19: chr13-110807776;