NM_001845.6:c.1728+57T>C

Variant names:

• chr13-110187081-A-G
• rs9521638
• NM_001845.6:c.1728+57T>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.1728+57T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 1,588,336 control chromosomes in the GnomAD database, including 108,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11633 hom., cov: 33)
  • Exomes 𝑓: 0.37 (97348 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.20
• Publications: 12 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 13-110187081-A-G is Benign according to our data. Variant chr13-110187081-A-G is described in ClinVar as Benign. ClinVar VariationId is 1293311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.1728+57T>C		intron_variant	Intron 25 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.1728+57T>C		intron_variant	Intron 25 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.389 AC: 59119 AN: 151826 Hom.: 11611 Cov.: 33

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.607

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.299

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.383

GnomAD4 exome AF: 0.366 AC: 525896 AN: 1436390 Hom.: 97348 AF XY: 0.365 AC XY: 261283 AN XY: 716260

African (AFR) AF: 0.450 AC: 14845 AN: 33018

American (AMR) AF: 0.404 AC: 18001 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 7901 AN: 25984

East Asian (EAS) AF: 0.434 AC: 17194 AN: 39572

South Asian (SAS) AF: 0.338 AC: 28968 AN: 85658

European-Finnish (FIN) AF: 0.345 AC: 18306 AN: 53100

Middle Eastern (MID) AF: 0.271 AC: 1538 AN: 5670

European-Non Finnish (NFE) AF: 0.365 AC: 397269 AN: 1089270

Other (OTH) AF: 0.368 AC: 21874 AN: 59514

GnomAD4 genome AF: 0.390 AC: 59196 AN: 151946 Hom.: 11633 Cov.: 33 AF XY: 0.388 AC XY: 28799 AN XY: 74274

African (AFR) AF: 0.448 AC: 18552 AN: 41438

American (AMR) AF: 0.376 AC: 5747 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1126 AN: 3466

East Asian (EAS) AF: 0.451 AC: 2318 AN: 5142

South Asian (SAS) AF: 0.343 AC: 1653 AN: 4814

European-Finnish (FIN) AF: 0.341 AC: 3603 AN: 10570

Middle Eastern (MID) AF: 0.291 AC: 85 AN: 292

European-Non Finnish (NFE) AF: 0.364 AC: 24742 AN: 67928

Other (OTH) AF: 0.388 AC: 816 AN: 2104

Alfa AF: 0.370 Hom.: 41193

Bravo AF: 0.397

Asia WGS AF: 0.421 AC: 1464 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	-0.91
CADD	Benign	0.46
DANN	Benign	0.22
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9521638; hg19: chr13-110839428; COSMIC: COSV65429670; COSMIC: COSV65429670;