rs496916

Variant names:

• chr13-110198667-G-C
• rs496916
• NM_001845.6:c.1121-36C>G

Your query was ambiguous. Multiple possible variants found:

• chr13-110198667-G-C
• chr13-110198667-G-A
• chr13-110198667-G-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.1121-36C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 1,612,806 control chromosomes in the GnomAD database, including 106,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9157 hom., cov: 32)
  • Exomes 𝑓: 0.36 (97724 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.622
• Publications: 18 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=-0.9).
• BP6: Variant 13-110198667-G-C is Benign according to our data. Variant chr13-110198667-G-C is described in ClinVar as Benign. ClinVar VariationId is 1262940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 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.1121-36C>G		intron	N/A	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.1121-36C>G		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.1121-36C>G		intron	N/A	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.1121-36C>G		intron	N/A	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.1121-36C>G		intron	N/A	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52219 AN: 151966 Hom.: 9160 Cov.: 32

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.374

GnomAD2 exomes AF: 0.362 AC: 90357 AN: 249514 AF XY: 0.371

Gnomad AFR exome AF: 0.302

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.443

Gnomad EAS exome AF: 0.470

Gnomad FIN exome AF: 0.350

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.378

GnomAD4 exome AF: 0.362 AC: 528389 AN: 1460722 Hom.: 97724 Cov.: 39 AF XY: 0.365 AC XY: 265023 AN XY: 726682

African (AFR) AF: 0.296 AC: 9913 AN: 33470

American (AMR) AF: 0.255 AC: 11392 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 11469 AN: 26132

East Asian (EAS) AF: 0.511 AC: 20296 AN: 39686

South Asian (SAS) AF: 0.445 AC: 38392 AN: 86198

European-Finnish (FIN) AF: 0.348 AC: 18384 AN: 52842

Middle Eastern (MID) AF: 0.480 AC: 2769 AN: 5766

European-Non Finnish (NFE) AF: 0.354 AC: 393086 AN: 1111566

Other (OTH) AF: 0.376 AC: 22688 AN: 60362

GnomAD4 genome AF: 0.343 AC: 52229 AN: 152084 Hom.: 9157 Cov.: 32 AF XY: 0.346 AC XY: 25730 AN XY: 74322

African (AFR) AF: 0.304 AC: 12623 AN: 41504

American (AMR) AF: 0.304 AC: 4649 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1440 AN: 3470

East Asian (EAS) AF: 0.476 AC: 2457 AN: 5162

South Asian (SAS) AF: 0.460 AC: 2215 AN: 4812

European-Finnish (FIN) AF: 0.353 AC: 3729 AN: 10560

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 24011 AN: 67982

Other (OTH) AF: 0.372 AC: 784 AN: 2108

Alfa AF: 0.294 Hom.: 1232

Bravo AF: 0.336

Asia WGS AF: 0.462 AC: 1605 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	-0.90
CADD	Benign	0.43
DANN	Benign	0.49
PhyloP100		-0.62
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: rs496916; hg19: chr13-110851014; COSMIC: COSV65422868;