13-110205476-C-T

Variant names:

• chr13-110205476-C-T
• rs482757
• NM_001845.6:c.903+18G>A

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.903+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 1,612,206 control chromosomes in the GnomAD database, including 325,047 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26219 hom., cov: 32)
  • Exomes 𝑓: 0.64 (298828 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.61
• Publications: 15 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=-0.89).
• BP6: Variant 13-110205476-C-T is Benign according to our data. Variant chr13-110205476-C-T is described in ClinVar as Benign. ClinVar VariationId is 258266.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.903+18G>A		intron	N/A	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.903+18G>A		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.903+18G>A		intron	N/A	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.903+18G>A		intron	N/A	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.903+18G>A		intron	N/A	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87124 AN: 151054 Hom.: 26222 Cov.: 32

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.700

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.620

GnomAD2 exomes AF: 0.619 AC: 155701 AN: 251374 AF XY: 0.630

Gnomad AFR exome AF: 0.423

Gnomad AMR exome AF: 0.497

Gnomad ASJ exome AF: 0.702

Gnomad EAS exome AF: 0.762

Gnomad FIN exome AF: 0.602

Gnomad NFE exome AF: 0.640

Gnomad OTH exome AF: 0.639

GnomAD4 exome AF: 0.637 AC: 930058 AN: 1461036 Hom.: 298828 Cov.: 51 AF XY: 0.639 AC XY: 464541 AN XY: 726856

African (AFR) AF: 0.410 AC: 13567 AN: 33102

American (AMR) AF: 0.500 AC: 22337 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 18410 AN: 26134

East Asian (EAS) AF: 0.774 AC: 30741 AN: 39698

South Asian (SAS) AF: 0.674 AC: 58125 AN: 86254

European-Finnish (FIN) AF: 0.603 AC: 32189 AN: 53418

Middle Eastern (MID) AF: 0.658 AC: 3792 AN: 5764

European-Non Finnish (NFE) AF: 0.641 AC: 712400 AN: 1111628

Other (OTH) AF: 0.638 AC: 38497 AN: 60330

GnomAD4 genome AF: 0.576 AC: 87137 AN: 151170 Hom.: 26219 Cov.: 32 AF XY: 0.578 AC XY: 42736 AN XY: 73926

African (AFR) AF: 0.426 AC: 17304 AN: 40610

American (AMR) AF: 0.543 AC: 8294 AN: 15264

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

East Asian (EAS) AF: 0.762 AC: 3940 AN: 5170

South Asian (SAS) AF: 0.690 AC: 3328 AN: 4820

European-Finnish (FIN) AF: 0.605 AC: 6396 AN: 10568

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.636 AC: 43247 AN: 67966

Other (OTH) AF: 0.616 AC: 1294 AN: 2100

Alfa AF: 0.618 Hom.: 82924

Bravo AF: 0.564

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
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (1)
-	-	1	Brain small vessel disease 1 with or without ocular anomalies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.13
DANN	Benign	0.38
PhyloP100		-1.6
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: rs482757; hg19: chr13-110857823; COSMIC: COSV104687933;