chr13-110167239-G-A

Variant names:

• chr13-110167239-G-A
• rs589985
• NM_001845.6:c.3877-9C>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.3877-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 1,601,826 control chromosomes in the GnomAD database, including 355,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31769 hom., cov: 31)
  • Exomes 𝑓: 0.67 (323539 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Scores: Splicing: ADA: 0.00001695
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.608
• 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=-0.9).
• BP6: Variant 13-110167239-G-A is Benign according to our data. Variant chr13-110167239-G-A is described in ClinVar as Benign. ClinVar VariationId is 258253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.709 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.3877-9C>T		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.3877-9C>T		intron	N/A	ENSP00000364979.4
	COL4A1	ENST00000650424.2		c.3877-9C>T		intron	N/A	ENSP00000497477.2
	COL4A1	ENST00000933608.1		c.3778-9C>T		intron	N/A	ENSP00000603667.1

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97688 AN: 151776 Hom.: 31752 Cov.: 31

Gnomad AFR AF: 0.565

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.637

GnomAD2 exomes AF: 0.680 AC: 170857 AN: 251100 AF XY: 0.676

Gnomad AFR exome AF: 0.557

Gnomad AMR exome AF: 0.813

Gnomad ASJ exome AF: 0.620

Gnomad EAS exome AF: 0.648

Gnomad FIN exome AF: 0.740

Gnomad NFE exome AF: 0.660

Gnomad OTH exome AF: 0.654

GnomAD4 exome AF: 0.666 AC: 965364 AN: 1449932 Hom.: 323539 Cov.: 33 AF XY: 0.665 AC XY: 480392 AN XY: 721984

African (AFR) AF: 0.553 AC: 18382 AN: 33238

American (AMR) AF: 0.801 AC: 35816 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 16202 AN: 26082

East Asian (EAS) AF: 0.677 AC: 26801 AN: 39612

South Asian (SAS) AF: 0.677 AC: 58273 AN: 86046

European-Finnish (FIN) AF: 0.735 AC: 39236 AN: 53374

Middle Eastern (MID) AF: 0.616 AC: 3541 AN: 5748

European-Non Finnish (NFE) AF: 0.660 AC: 727293 AN: 1101128

Other (OTH) AF: 0.664 AC: 39820 AN: 59998

GnomAD4 genome AF: 0.644 AC: 97748 AN: 151894 Hom.: 31769 Cov.: 31 AF XY: 0.648 AC XY: 48145 AN XY: 74246

African (AFR) AF: 0.564 AC: 23347 AN: 41372

American (AMR) AF: 0.720 AC: 10997 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 2136 AN: 3468

East Asian (EAS) AF: 0.670 AC: 3454 AN: 5158

South Asian (SAS) AF: 0.694 AC: 3334 AN: 4804

European-Finnish (FIN) AF: 0.732 AC: 7732 AN: 10558

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.659 AC: 44788 AN: 67954

Other (OTH) AF: 0.641 AC: 1349 AN: 2106

Alfa AF: 0.646 Hom.: 19241

Bravo AF: 0.641

Asia WGS AF: 0.706 AC: 2458 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (2)
-	-	2	Brain small vessel disease 1 with or without ocular anomalies (2)
-	-	2	not provided (2)
-	-	1	Porencephalic cyst (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.24
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0
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: rs589985; hg19: chr13-110819586;