rs9588112

Variant names:

• chr13-110195219-C-T
• rs9588112
• NM_001845.6:c.1286-101G>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.1286-101G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0887 in 945,432 control chromosomes in the GnomAD database, including 4,770 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1451 hom., cov: 32)
  • Exomes 𝑓: 0.083 (3319 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.17
• Publications: 2 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=-0.94).
• BP6: Variant 13-110195219-C-T is Benign according to our data. Variant chr13-110195219-C-T is described in ClinVar as Benign. ClinVar VariationId is 1293369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.225 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.1286-101G>A		intron	N/A	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.1286-101G>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.1286-101G>A		intron	N/A	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.1286-101G>A		intron	N/A	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.1286-101G>A		intron	N/A	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18201 AN: 152024 Hom.: 1446 Cov.: 32

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.0698

Gnomad FIN AF: 0.0573

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0761

Gnomad OTH AF: 0.101

GnomAD4 exome AF: 0.0827 AC: 65642 AN: 793290 Hom.: 3319 AF XY: 0.0813 AC XY: 33740 AN XY: 414944

African (AFR) AF: 0.231 AC: 4696 AN: 20320

American (AMR) AF: 0.134 AC: 4887 AN: 36540

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 604 AN: 21456

East Asian (EAS) AF: 0.150 AC: 5185 AN: 34476

South Asian (SAS) AF: 0.0706 AC: 4834 AN: 68436

European-Finnish (FIN) AF: 0.0626 AC: 3153 AN: 50330

Middle Eastern (MID) AF: 0.0346 AC: 153 AN: 4426

European-Non Finnish (NFE) AF: 0.0749 AC: 38870 AN: 519266

Other (OTH) AF: 0.0857 AC: 3260 AN: 38040

GnomAD4 genome AF: 0.120 AC: 18247 AN: 152142 Hom.: 1451 Cov.: 32 AF XY: 0.118 AC XY: 8762 AN XY: 74376

African (AFR) AF: 0.229 AC: 9479 AN: 41468

American (AMR) AF: 0.105 AC: 1609 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 97 AN: 3468

East Asian (EAS) AF: 0.128 AC: 660 AN: 5168

South Asian (SAS) AF: 0.0696 AC: 335 AN: 4812

European-Finnish (FIN) AF: 0.0573 AC: 607 AN: 10600

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0761 AC: 5177 AN: 68016

Other (OTH) AF: 0.101 AC: 213 AN: 2114

Alfa AF: 0.0890 Hom.: 127

Bravo AF: 0.129

Asia WGS AF: 0.107 AC: 371 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	-0.94
CADD	Benign	0.76
DANN	Benign	0.43
PhyloP100		-1.2
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: rs9588112; hg19: chr13-110847566;