rs648735

Variant names:

• chr13-110203833-A-G
• rs648735
• NM_001845.6:c.958-226T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-110203833-A-G
• chr13-110203833-A-C
• chr13-110203833-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001845.6(COL4A1):​c.958-226T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.574 in 151,936 control chromosomes in the GnomAD database, including 25,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.57 (25999 hom., cov: 33)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.67
• Publications: 3 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: Ambry Genetics, Orphanet, G2P, Genomics England PanelApp
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 13-110203833-A-G is Benign according to our data. Variant chr13-110203833-A-G is described in ClinVar as Benign. ClinVar VariationId is 1293040.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001845.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	NM_001845.6	MANE Select	c.958-226T>C		intron	N/A	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.958-226T>C		intron	N/A	NP_001290039.1	P02462-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.958-226T>C		intron	N/A	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.958-226T>C		intron	N/A	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.958-226T>C		intron	N/A	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87213 AN: 151818 Hom.: 26003 Cov.: 33

Gnomad AFR AF: 0.414

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.698

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.643

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.618

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.574 AC: 87223 AN: 151936 Hom.: 25999 Cov.: 33 AF XY: 0.576 AC XY: 42782 AN XY: 74284

African (AFR) AF: 0.414 AC: 17096 AN: 41294

American (AMR) AF: 0.542 AC: 8294 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.698 AC: 2424 AN: 3472

East Asian (EAS) AF: 0.762 AC: 3949 AN: 5182

South Asian (SAS) AF: 0.700 AC: 3376 AN: 4822

European-Finnish (FIN) AF: 0.610 AC: 6436 AN: 10558

Middle Eastern (MID) AF: 0.634 AC: 185 AN: 292

European-Non Finnish (NFE) AF: 0.638 AC: 43365 AN: 68002

Other (OTH) AF: 0.615 AC: 1298 AN: 2112

Alfa AF: 0.580 Hom.: 3414

Bravo AF: 0.562

Asia WGS AF: 0.683 AC: 2376 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.022
DANN	Benign	0.22
PhyloP100		-2.7
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: rs648735; hg19: chr13-110856180;