13-110172627-C-G

Variant names:

• chr13-110172627-C-G
• rs2289799
• NM_001845.6:c.3556+93G>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.3556+93G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 1,250,774 control chromosomes in the GnomAD database, including 81,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9064 hom., cov: 33)
  • Exomes 𝑓: 0.36 (72714 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.531
• Publications: 4 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 13-110172627-C-G is Benign according to our data. Variant chr13-110172627-C-G is described in ClinVar as Benign. ClinVar VariationId is 1261484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.3556+93G>C		intron_variant	Intron 41 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.3556+93G>C		intron_variant	Intron 41 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52263 AN: 151970 Hom.: 9047 Cov.: 33

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.355

Gnomad MID AF: 0.303

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.350

GnomAD4 exome AF: 0.360 AC: 396049 AN: 1098686 Hom.: 72714 AF XY: 0.361 AC XY: 203308 AN XY: 563756

African (AFR) AF: 0.297 AC: 7805 AN: 26260

American (AMR) AF: 0.390 AC: 17243 AN: 44236

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 7637 AN: 23948

East Asian (EAS) AF: 0.263 AC: 9966 AN: 37954

South Asian (SAS) AF: 0.364 AC: 28806 AN: 79106

European-Finnish (FIN) AF: 0.357 AC: 18988 AN: 53186

Middle Eastern (MID) AF: 0.256 AC: 1201 AN: 4692

European-Non Finnish (NFE) AF: 0.368 AC: 287423 AN: 780980

Other (OTH) AF: 0.351 AC: 16980 AN: 48324

GnomAD4 genome AF: 0.344 AC: 52313 AN: 152088 Hom.: 9064 Cov.: 33 AF XY: 0.344 AC XY: 25565 AN XY: 74346

African (AFR) AF: 0.297 AC: 12304 AN: 41484

American (AMR) AF: 0.359 AC: 5495 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 1180 AN: 3470

East Asian (EAS) AF: 0.293 AC: 1508 AN: 5150

South Asian (SAS) AF: 0.361 AC: 1741 AN: 4824

European-Finnish (FIN) AF: 0.355 AC: 3753 AN: 10580

Middle Eastern (MID) AF: 0.298 AC: 87 AN: 292

European-Non Finnish (NFE) AF: 0.369 AC: 25073 AN: 67972

Other (OTH) AF: 0.355 AC: 749 AN: 2108

Alfa AF: 0.362 Hom.: 1282

Bravo AF: 0.342

Asia WGS AF: 0.359 AC: 1246 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.34
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: rs2289799; hg19: chr13-110824974; COSMIC: COSV65429661;