rs16975491

Variant names:

• chr13-110181217-C-T
• rs16975491
• NM_001845.6:c.2193+75G>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.2193+75G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,453,128 control chromosomes in the GnomAD database, including 92,463 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (8866 hom., cov: 32)
  • Exomes 𝑓: 0.36 (83597 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.35
• Publications: 6 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=-1.02).
• BP6: Variant 13-110181217-C-T is Benign according to our data. Variant chr13-110181217-C-T is described in ClinVar as Benign. ClinVar VariationId is 1293320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.2193+75G>A		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.2193+75G>A		intron_variant	Intron 29 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51642 AN: 151884 Hom.: 8854 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.559

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.356

GnomAD4 exome AF: 0.356 AC: 462816 AN: 1301126 Hom.: 83597 AF XY: 0.357 AC XY: 233195 AN XY: 653972

African (AFR) AF: 0.270 AC: 8269 AN: 30640

American (AMR) AF: 0.390 AC: 17175 AN: 44014

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 7967 AN: 25028

East Asian (EAS) AF: 0.264 AC: 10224 AN: 38788

South Asian (SAS) AF: 0.372 AC: 30702 AN: 82530

European-Finnish (FIN) AF: 0.356 AC: 18883 AN: 53104

Middle Eastern (MID) AF: 0.259 AC: 1357 AN: 5248

European-Non Finnish (NFE) AF: 0.361 AC: 349013 AN: 966706

Other (OTH) AF: 0.349 AC: 19226 AN: 55068

GnomAD4 genome AF: 0.340 AC: 51692 AN: 152002 Hom.: 8866 Cov.: 32 AF XY: 0.340 AC XY: 25289 AN XY: 74286

African (AFR) AF: 0.279 AC: 11567 AN: 41460

American (AMR) AF: 0.363 AC: 5551 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1188 AN: 3466

East Asian (EAS) AF: 0.297 AC: 1539 AN: 5176

South Asian (SAS) AF: 0.371 AC: 1789 AN: 4826

European-Finnish (FIN) AF: 0.351 AC: 3698 AN: 10530

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.368 AC: 25001 AN: 67934

Other (OTH) AF: 0.362 AC: 764 AN: 2112

Alfa AF: 0.354 Hom.: 1283

Bravo AF: 0.338

Asia WGS AF: 0.362 AC: 1256 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	-1.0
CADD	Benign	0.010
DANN	Benign	0.40
PhyloP100		-2.4
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: rs16975491; hg19: chr13-110833564; COSMIC: COSV65427750;