NM_001845.6:c.469-127C>T

Variant names:

• chr13-110210339-G-A
• rs2166208
• NM_001845.6:c.469-127C>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.469-127C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0837 in 850,754 control chromosomes in the GnomAD database, including 3,429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (995 hom., cov: 32)
  • Exomes 𝑓: 0.079 (2434 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0180
• 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: 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=-0.82).
• BP6: Variant 13-110210339-G-A is Benign according to our data. Variant chr13-110210339-G-A is described in ClinVar as Benign. ClinVar VariationId is 1262395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.469-127C>T		intron_variant	Intron 8 of 51	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.469-127C>T		intron_variant	Intron 8 of 24		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.469-127C>T		intron_variant	Intron 8 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15985 AN: 151916 Hom.: 993 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0724

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.0780

Gnomad SAS AF: 0.0778

Gnomad FIN AF: 0.0644

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0812

Gnomad OTH AF: 0.0990

GnomAD4 exome AF: 0.0791 AC: 55237 AN: 698720 Hom.: 2434 AF XY: 0.0791 AC XY: 29148 AN XY: 368532

African (AFR) AF: 0.188 AC: 3383 AN: 18020

American (AMR) AF: 0.0615 AC: 2114 AN: 34350

Ashkenazi Jewish (ASJ) AF: 0.0451 AC: 927 AN: 20534

East Asian (EAS) AF: 0.0736 AC: 2408 AN: 32696

South Asian (SAS) AF: 0.0768 AC: 4936 AN: 64230

European-Finnish (FIN) AF: 0.0736 AC: 3062 AN: 41620

Middle Eastern (MID) AF: 0.0377 AC: 104 AN: 2760

European-Non Finnish (NFE) AF: 0.0787 AC: 35380 AN: 449452

Other (OTH) AF: 0.0834 AC: 2923 AN: 35058

GnomAD4 genome AF: 0.105 AC: 16013 AN: 152034 Hom.: 995 Cov.: 32 AF XY: 0.103 AC XY: 7646 AN XY: 74330

African (AFR) AF: 0.181 AC: 7485 AN: 41442

American (AMR) AF: 0.0724 AC: 1106 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 162 AN: 3466

East Asian (EAS) AF: 0.0782 AC: 404 AN: 5168

South Asian (SAS) AF: 0.0772 AC: 372 AN: 4816

European-Finnish (FIN) AF: 0.0644 AC: 681 AN: 10582

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0812 AC: 5519 AN: 67956

Other (OTH) AF: 0.0985 AC: 208 AN: 2112

Alfa AF: 0.119 Hom.: 489

Bravo AF: 0.110

Asia WGS AF: 0.0900 AC: 311 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.9
DANN	Benign	0.56
PhyloP100		-0.018
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: rs2166208; hg19: chr13-110862686;