rs2275843

Variant names:

• chr13-110161185-G-A
• rs2275843
• NM_001845.6:c.4640+7C>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.4640+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,611,832 control chromosomes in the GnomAD database, including 21,864 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1874 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19990 hom.)
• Consequence: COL4A1 NM_001845.6 splice_region, intron
• Scores: Splicing: ADA: 0.00001050
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.68
• Publications: 19 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: G2P, Ambry Genetics, PanelApp Australia, Orphanet, Genomics England PanelApp
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
• 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=-0.91).
• BP6: Variant 13-110161185-G-A is Benign according to our data. Variant chr13-110161185-G-A is described in ClinVar as Benign. ClinVar VariationId is 258257.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+7C>T		splice_region intron	N/A	NP_001836.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.4640+7C>T		splice_region intron	N/A	ENSP00000364979.4
	COL4A1	ENST00000650424.2		c.4640+7C>T		splice_region intron	N/A	ENSP00000497477.2
	COL4A1	ENST00000933608.1		c.4541+7C>T		splice_region intron	N/A	ENSP00000603667.1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23209 AN: 151970 Hom.: 1875 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: 0.324

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.167 AC: 41854 AN: 251118 AF XY: 0.166

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.304

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.180

GnomAD4 exome AF: 0.162 AC: 235921 AN: 1459744 Hom.: 19990 Cov.: 31 AF XY: 0.162 AC XY: 117404 AN XY: 726296

African (AFR) AF: 0.119 AC: 3965 AN: 33442

American (AMR) AF: 0.180 AC: 8038 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4466 AN: 26126

East Asian (EAS) AF: 0.312 AC: 12381 AN: 39664

South Asian (SAS) AF: 0.177 AC: 15277 AN: 86134

European-Finnish (FIN) AF: 0.110 AC: 5893 AN: 53404

Middle Eastern (MID) AF: 0.233 AC: 1334 AN: 5718

European-Non Finnish (NFE) AF: 0.157 AC: 174145 AN: 1110254

Other (OTH) AF: 0.173 AC: 10422 AN: 60308

GnomAD4 genome AF: 0.153 AC: 23221 AN: 152088 Hom.: 1874 Cov.: 33 AF XY: 0.154 AC XY: 11431 AN XY: 74354

African (AFR) AF: 0.117 AC: 4853 AN: 41494

American (AMR) AF: 0.189 AC: 2890 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 537 AN: 3468

East Asian (EAS) AF: 0.323 AC: 1665 AN: 5150

South Asian (SAS) AF: 0.192 AC: 924 AN: 4824

European-Finnish (FIN) AF: 0.108 AC: 1147 AN: 10586

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

European-Non Finnish (NFE) AF: 0.156 AC: 10629 AN: 67982

Other (OTH) AF: 0.184 AC: 387 AN: 2108

Alfa AF: 0.161 Hom.: 8925

Bravo AF: 0.157

Asia WGS AF: 0.263 AC: 912 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.11
DANN	Benign	0.35
PhyloP100		-3.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000010
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.010		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: rs2275843; hg19: chr13-110813532; COSMIC: COSV65423062; COSMIC: COSV65423062;