rs2298240

Variant names:

• chr13-110163326-C-G
• rs2298240
• NM_001845.6:c.4249+137G>C

Your query was ambiguous. Multiple possible variants found:

• chr13-110163326-C-G
• chr13-110163326-C-T

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.4249+137G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 764,244 control chromosomes in the GnomAD database, including 5,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (793 hom., cov: 33)
  • Exomes 𝑓: 0.11 (4318 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.311
• 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=-0.84).
• BP6: Variant 13-110163326-C-G is Benign according to our data. Variant chr13-110163326-C-G is described in ClinVar as Benign. ClinVar VariationId is 1231553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.4249+137G>C		intron_variant	Intron 47 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.4249+137G>C		intron_variant	Intron 47 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.0883 AC: 13433 AN: 152144 Hom.: 794 Cov.: 33

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.0907

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0966

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.100

GnomAD4 exome AF: 0.113 AC: 69083 AN: 611982 Hom.: 4318 AF XY: 0.115 AC XY: 37389 AN XY: 326444

African (AFR) AF: 0.0209 AC: 343 AN: 16426

American (AMR) AF: 0.0758 AC: 2586 AN: 34098

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 2501 AN: 20100

East Asian (EAS) AF: 0.0326 AC: 1049 AN: 32200

South Asian (SAS) AF: 0.119 AC: 7444 AN: 62702

European-Finnish (FIN) AF: 0.104 AC: 4985 AN: 48060

Middle Eastern (MID) AF: 0.0567 AC: 234 AN: 4124

European-Non Finnish (NFE) AF: 0.128 AC: 46470 AN: 362172

Other (OTH) AF: 0.108 AC: 3471 AN: 32100

GnomAD4 genome AF: 0.0882 AC: 13426 AN: 152262 Hom.: 793 Cov.: 33 AF XY: 0.0867 AC XY: 6452 AN XY: 74450

African (AFR) AF: 0.0228 AC: 947 AN: 41556

American (AMR) AF: 0.0906 AC: 1385 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 465 AN: 3468

East Asian (EAS) AF: 0.0141 AC: 73 AN: 5176

South Asian (SAS) AF: 0.120 AC: 581 AN: 4828

European-Finnish (FIN) AF: 0.0966 AC: 1024 AN: 10604

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8651 AN: 68016

Other (OTH) AF: 0.0993 AC: 210 AN: 2114

Alfa AF: 0.0350 Hom.: 36

Bravo AF: 0.0841

Asia WGS AF: 0.0650 AC: 225 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

- -

Jul 07, 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	-0.84
CADD	Benign	9.0
DANN	Benign	0.53
PhyloP100		0.31
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: rs2298240; hg19: chr13-110815673;