rs13260

Variant names:

• chr13-110149776-G-T
• rs13260
• NM_001845.6:c.*587C>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.*587C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 152,930 control chromosomes in the GnomAD database, including 1,903 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1897 hom., cov: 33)
  • Exomes 𝑓: 0.073 (6 hom.)
• Consequence: COL4A1 NM_001845.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.11
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 13-110149776-G-T is Benign according to our data. Variant chr13-110149776-G-T is described in ClinVar as Benign. ClinVar VariationId is 311011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.232 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.*587C>A		3_prime_UTR	Exon 52 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.*587C>A		3_prime_UTR	Exon 52 of 52	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000650424.2		c.*587C>A		3_prime_UTR	Exon 52 of 52	ENSP00000497477.2	A0A3B3ISV3
	COL4A1	ENST00000933608.1		c.*587C>A		3_prime_UTR	Exon 51 of 51	ENSP00000603667.1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20987 AN: 151828 Hom.: 1884 Cov.: 33

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.00463

Gnomad SAS AF: 0.0719

Gnomad FIN AF: 0.0839

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0918

Gnomad OTH AF: 0.136

GnomAD4 exome AF: 0.0729 AC: 72 AN: 988 Hom.: 6 Cov.: 0 AF XY: 0.0819 AC XY: 47 AN XY: 574

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.135 AC: 17 AN: 126

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 12

South Asian (SAS) AF: 0.0167 AC: 1 AN: 60

European-Finnish (FIN) AF: 0.0963 AC: 26 AN: 270

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0551 AC: 27 AN: 490

Other (OTH) AF: 0.0357 AC: 1 AN: 28

GnomAD4 genome AF: 0.138 AC: 21035 AN: 151942 Hom.: 1897 Cov.: 33 AF XY: 0.138 AC XY: 10269 AN XY: 74290

African (AFR) AF: 0.236 AC: 9784 AN: 41424

American (AMR) AF: 0.196 AC: 2993 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 433 AN: 3466

East Asian (EAS) AF: 0.00444 AC: 23 AN: 5176

South Asian (SAS) AF: 0.0718 AC: 346 AN: 4822

European-Finnish (FIN) AF: 0.0839 AC: 883 AN: 10522

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

European-Non Finnish (NFE) AF: 0.0918 AC: 6239 AN: 67950

Other (OTH) AF: 0.135 AC: 284 AN: 2102

Alfa AF: 0.108 Hom.: 1416

Bravo AF: 0.152

Asia WGS AF: 0.0670 AC: 233 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	12
DANN	Benign	0.41
PhyloP100		1.1
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: rs13260; hg19: chr13-110802123;