rs650724

Variant names:

• chr13-110152462-G-A
• rs650724
• NM_001845.6:c.4800C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-110152462-G-A
• chr13-110152462-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001845.6(COL4A1):​c.4800C>T​(p.Ser1600Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,613,748 control chromosomes in the GnomAD database, including 9,606 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1600S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.13 (1605 hom., cov: 33)
  • Exomes 𝑓: 0.097 (8001 hom.)
• Consequence: COL4A1 NM_001845.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.103
• Publications: 16 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 13-110152462-G-A is Benign according to our data. Variant chr13-110152462-G-A is described in ClinVar as Benign. ClinVar VariationId is 258260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.103 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 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.4800C>T	p.Ser1600Ser	synonymous	Exon 51 of 52	NP_001836.3	P02462-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.4800C>T	p.Ser1600Ser	synonymous	Exon 51 of 52	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000650424.2		c.4800C>T	p.Ser1600Ser	synonymous	Exon 51 of 52	ENSP00000497477.2	A0A3B3ISV3
	COL4A1	ENST00000933608.1		c.4701C>T	p.Ser1567Ser	synonymous	Exon 50 of 51	ENSP00000603667.1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19848 AN: 152128 Hom.: 1593 Cov.: 33

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.0720

Gnomad FIN AF: 0.0833

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0942

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.113 AC: 28294 AN: 250762 AF XY: 0.107

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.226

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.00337

Gnomad FIN exome AF: 0.0852

Gnomad NFE exome AF: 0.0966

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.0969 AC: 141563 AN: 1461502 Hom.: 8001 Cov.: 32 AF XY: 0.0956 AC XY: 69528 AN XY: 727052

African (AFR) AF: 0.212 AC: 7111 AN: 33480

American (AMR) AF: 0.224 AC: 10024 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 3141 AN: 26130

East Asian (EAS) AF: 0.00217 AC: 86 AN: 39700

South Asian (SAS) AF: 0.0775 AC: 6680 AN: 86220

European-Finnish (FIN) AF: 0.0847 AC: 4509 AN: 53238

Middle Eastern (MID) AF: 0.140 AC: 800 AN: 5732

European-Non Finnish (NFE) AF: 0.0928 AC: 103178 AN: 1111934

Other (OTH) AF: 0.0999 AC: 6034 AN: 60386

GnomAD4 genome AF: 0.131 AC: 19895 AN: 152246 Hom.: 1605 Cov.: 33 AF XY: 0.131 AC XY: 9723 AN XY: 74456

African (AFR) AF: 0.205 AC: 8524 AN: 41532

American (AMR) AF: 0.193 AC: 2952 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 435 AN: 3472

East Asian (EAS) AF: 0.00443 AC: 23 AN: 5188

South Asian (SAS) AF: 0.0718 AC: 347 AN: 4832

European-Finnish (FIN) AF: 0.0833 AC: 883 AN: 10600

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.0942 AC: 6407 AN: 68028

Other (OTH) AF: 0.130 AC: 274 AN: 2108

Alfa AF: 0.112 Hom.: 526

Bravo AF: 0.144

Asia WGS AF: 0.0680 AC: 237 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.105

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Brain small vessel disease 1 with or without ocular anomalies (3)
-	-	2	not provided (2)
-	-	1	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.1
DANN	Benign	0.47
PhyloP100		0.10
Mutation Taster		=78/22	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: rs650724; hg19: chr13-110804809; COSMIC: COSV65428107;