chr13-110192374-C-T

Variant names:

• chr13-110192374-C-T
• rs2241967
• NM_001845.6:c.1466-90G>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.1466-90G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 1,240,710 control chromosomes in the GnomAD database, including 135,536 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13351 hom., cov: 32)
  • Exomes 𝑓: 0.47 (122185 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0650
• Publications: 8 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=-0.87).
• BP6: Variant 13-110192374-C-T is Benign according to our data. Variant chr13-110192374-C-T is described in ClinVar as Benign. ClinVar VariationId is 1292612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.534 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	NM_001845.6	MANE Select	c.1466-90G>A		intron	N/A	NP_001836.3
	COL4A1	NM_001303110.2		c.1466-90G>A		intron	N/A	NP_001290039.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.1466-90G>A		intron	N/A	ENSP00000364979.4
	COL4A1	ENST00000543140.6	TSL:1	c.1466-90G>A		intron	N/A	ENSP00000443348.1
	COL4A1	ENST00000650424.2		c.1466-90G>A		intron	N/A	ENSP00000497477.2

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62588 AN: 151762 Hom.: 13356 Cov.: 32

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.369

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.464

GnomAD4 exome AF: 0.470 AC: 511773 AN: 1088830 Hom.: 122185 AF XY: 0.473 AC XY: 263101 AN XY: 555830

African (AFR) AF: 0.292 AC: 7680 AN: 26260

American (AMR) AF: 0.310 AC: 12318 AN: 39782

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 11935 AN: 23406

East Asian (EAS) AF: 0.540 AC: 20230 AN: 37440

South Asian (SAS) AF: 0.538 AC: 40961 AN: 76146

European-Finnish (FIN) AF: 0.424 AC: 21399 AN: 50478

Middle Eastern (MID) AF: 0.538 AC: 2749 AN: 5114

European-Non Finnish (NFE) AF: 0.475 AC: 371837 AN: 782160

Other (OTH) AF: 0.472 AC: 22664 AN: 48044

GnomAD4 genome AF: 0.412 AC: 62585 AN: 151880 Hom.: 13351 Cov.: 32 AF XY: 0.412 AC XY: 30554 AN XY: 74190

African (AFR) AF: 0.302 AC: 12514 AN: 41402

American (AMR) AF: 0.380 AC: 5801 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1711 AN: 3470

East Asian (EAS) AF: 0.485 AC: 2495 AN: 5148

South Asian (SAS) AF: 0.551 AC: 2653 AN: 4814

European-Finnish (FIN) AF: 0.414 AC: 4359 AN: 10530

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.465 AC: 31585 AN: 67946

Other (OTH) AF: 0.463 AC: 973 AN: 2102

Alfa AF: 0.442 Hom.: 22636

Bravo AF: 0.400

Asia WGS AF: 0.510 AC: 1772 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.87
CADD	Benign	6.1
DANN	Benign	0.33
PhyloP100		0.065
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: rs2241967; hg19: chr13-110844721; COSMIC: COSV65426235;