13-110161176-C-T

Variant names:

• chr13-110161176-C-T
• rs2275842
• NM_001845.6:c.4640+16G>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.4640+16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,610,684 control chromosomes in the GnomAD database, including 21,833 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1880 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19953 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0310
• Publications: 13 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=-0.83).
• BP6: Variant 13-110161176-C-T is Benign according to our data. Variant chr13-110161176-C-T is described in ClinVar as Benign. ClinVar VariationId is 258256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.31 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.4640+16G>A		intron	N/A	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.4640+16G>A		intron	N/A	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000650424.2		c.4640+16G>A		intron	N/A	ENSP00000497477.2	A0A3B3ISV3
	COL4A1	ENST00000933608.1		c.4541+16G>A		intron	N/A	ENSP00000603667.1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23223 AN: 152064 Hom.: 1881 Cov.: 33

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.166 AC: 41781 AN: 250984 AF XY: 0.166

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.303

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.180

GnomAD4 exome AF: 0.161 AC: 235388 AN: 1458502 Hom.: 19953 Cov.: 30 AF XY: 0.161 AC XY: 117161 AN XY: 725738

African (AFR) AF: 0.118 AC: 3953 AN: 33414

American (AMR) AF: 0.180 AC: 8030 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4467 AN: 26124

East Asian (EAS) AF: 0.312 AC: 12361 AN: 39650

South Asian (SAS) AF: 0.177 AC: 15257 AN: 86110

European-Finnish (FIN) AF: 0.110 AC: 5891 AN: 53396

Middle Eastern (MID) AF: 0.233 AC: 1318 AN: 5652

European-Non Finnish (NFE) AF: 0.157 AC: 173725 AN: 1109230

Other (OTH) AF: 0.172 AC: 10386 AN: 60244

GnomAD4 genome AF: 0.153 AC: 23235 AN: 152182 Hom.: 1880 Cov.: 33 AF XY: 0.154 AC XY: 11438 AN XY: 74402

African (AFR) AF: 0.117 AC: 4858 AN: 41518

American (AMR) AF: 0.189 AC: 2892 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 537 AN: 3470

East Asian (EAS) AF: 0.323 AC: 1666 AN: 5158

South Asian (SAS) AF: 0.191 AC: 920 AN: 4828

European-Finnish (FIN) AF: 0.108 AC: 1148 AN: 10600

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.156 AC: 10639 AN: 68010

Other (OTH) AF: 0.183 AC: 386 AN: 2110

Alfa AF: 0.153 Hom.: 330

Bravo AF: 0.158

Asia WGS AF: 0.261 AC: 906 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.37
PhyloP100		0.031
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: rs2275842; hg19: chr13-110813523; COSMIC: COSV65423059; COSMIC: COSV65423059;