rs2275845

Variant names:

• chr13-110170831-G-A
• rs2275845
• NM_001845.6:c.3557-99C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-110170831-G-A
• chr13-110170831-G-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.3557-99C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0726 in 1,300,796 control chromosomes in the GnomAD database, including 3,747 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (340 hom., cov: 33)
  • Exomes 𝑓: 0.073 (3407 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.509
• 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=-0.87).
• BP6: Variant 13-110170831-G-A is Benign according to our data. Variant chr13-110170831-G-A is described in ClinVar as Benign. ClinVar VariationId is 1241907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.3557-99C>T		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.3557-99C>T		intron_variant	Intron 41 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.0672 AC: 10229 AN: 152184 Hom.: 339 Cov.: 33

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0815

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.0610

Gnomad FIN AF: 0.0923

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0711

Gnomad OTH AF: 0.0745

GnomAD4 exome AF: 0.0733 AC: 84153 AN: 1148494 Hom.: 3407 AF XY: 0.0727 AC XY: 42381 AN XY: 582964

African (AFR) AF: 0.0468 AC: 1295 AN: 27686

American (AMR) AF: 0.117 AC: 4684 AN: 40186

Ashkenazi Jewish (ASJ) AF: 0.0168 AC: 401 AN: 23916

East Asian (EAS) AF: 0.134 AC: 5046 AN: 37784

South Asian (SAS) AF: 0.0631 AC: 4923 AN: 77978

European-Finnish (FIN) AF: 0.0881 AC: 3665 AN: 41616

Middle Eastern (MID) AF: 0.0190 AC: 97 AN: 5104

European-Non Finnish (NFE) AF: 0.0720 AC: 60802 AN: 843970

Other (OTH) AF: 0.0645 AC: 3240 AN: 50254

GnomAD4 genome AF: 0.0672 AC: 10242 AN: 152302 Hom.: 340 Cov.: 33 AF XY: 0.0694 AC XY: 5165 AN XY: 74476

African (AFR) AF: 0.0484 AC: 2011 AN: 41562

American (AMR) AF: 0.0815 AC: 1248 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3472

East Asian (EAS) AF: 0.114 AC: 592 AN: 5180

South Asian (SAS) AF: 0.0609 AC: 294 AN: 4830

European-Finnish (FIN) AF: 0.0923 AC: 980 AN: 10618

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0711 AC: 4838 AN: 68014

Other (OTH) AF: 0.0742 AC: 157 AN: 2116

Alfa AF: 0.0679 Hom.: 128

Bravo AF: 0.0675

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	-0.87
CADD	Benign	0.83
DANN	Benign	0.53
PhyloP100		-0.51
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: rs2275845; hg19: chr13-110823178; COSMIC: COSV65430820;