rs648263

Variant names:

• chr13-110203738-A-G
• rs648263
• NM_001845.6:c.958-131T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-110203738-A-G
• chr13-110203738-A-C
• chr13-110203738-A-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.958-131T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 945,988 control chromosomes in the GnomAD database, including 192,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (26043 hom., cov: 34)
  • Exomes 𝑓: 0.64 (166098 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.61
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 13-110203738-A-G is Benign according to our data. Variant chr13-110203738-A-G is described in ClinVar as Benign. ClinVar VariationId is 1293039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 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.958-131T>C		intron	N/A	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.958-131T>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.958-131T>C		intron	N/A	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.958-131T>C		intron	N/A	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.958-131T>C		intron	N/A	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87296 AN: 152034 Hom.: 26047 Cov.: 34

Gnomad AFR AF: 0.413

Gnomad AMI AF: 0.879

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.700

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.699

Gnomad FIN AF: 0.609

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.619

GnomAD4 exome AF: 0.643 AC: 510283 AN: 793836 Hom.: 166098 AF XY: 0.646 AC XY: 268639 AN XY: 415954

African (AFR) AF: 0.406 AC: 8163 AN: 20086

American (AMR) AF: 0.503 AC: 18523 AN: 36850

Ashkenazi Jewish (ASJ) AF: 0.708 AC: 14665 AN: 20720

East Asian (EAS) AF: 0.776 AC: 27429 AN: 35344

South Asian (SAS) AF: 0.684 AC: 46042 AN: 67300

European-Finnish (FIN) AF: 0.607 AC: 26692 AN: 43984

Middle Eastern (MID) AF: 0.663 AC: 2820 AN: 4256

European-Non Finnish (NFE) AF: 0.648 AC: 341546 AN: 527012

Other (OTH) AF: 0.637 AC: 24403 AN: 38284

GnomAD4 genome AF: 0.574 AC: 87306 AN: 152152 Hom.: 26043 Cov.: 34 AF XY: 0.576 AC XY: 42825 AN XY: 74388

African (AFR) AF: 0.412 AC: 17110 AN: 41486

American (AMR) AF: 0.544 AC: 8323 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 2429 AN: 3470

East Asian (EAS) AF: 0.762 AC: 3948 AN: 5180

South Asian (SAS) AF: 0.699 AC: 3376 AN: 4828

European-Finnish (FIN) AF: 0.609 AC: 6438 AN: 10572

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.638 AC: 43395 AN: 68002

Other (OTH) AF: 0.615 AC: 1302 AN: 2116

Alfa AF: 0.450 Hom.: 1327

Bravo AF: 0.563

Asia WGS AF: 0.684 AC: 2379 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.40
DANN	Benign	0.19
PhyloP100		-2.6
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: rs648263; hg19: chr13-110856085;