13-110306946-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001845.6(COL4A1):c.82A>G(p.Lys28Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000758 in 1,319,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

COL4A1
NM_001845.6 missense, splice_region

Scores

Splicing: ADA: 0.0007780

Clinical Significance

Uncertain significance criteria provided, single submitter U:3

Conservation

PhyloP100: 1.22

Variant links:

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 links:

COL4A2 (HGNC:2203): (collagen type IV alpha 2 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. The C-terminal portion of the protein, known as canstatin, is an inhibitor of angiogenesis and tumor growth. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jul 2008]

COL4A2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, COL4A1

BP4

Computational evidence support a benign effect (MetaRNN=0.3029735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6 linkuse as main transcript	c.82A>G	p.Lys28Glu	missense_variant, splice_region_variant	1/52	ENST00000375820.10
COL4A1	NM_001303110.2 linkuse as main transcript	c.82A>G	p.Lys28Glu	missense_variant, splice_region_variant	1/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10 linkuse as main transcript	c.82A>G	p.Lys28Glu	missense_variant, splice_region_variant	1/52	1	NM_001845.6	P1	P02462-1
COL4A1	ENST00000543140.6 linkuse as main transcript	c.82A>G	p.Lys28Glu	missense_variant, splice_region_variant	1/25	1			P02462-2
COL4A2	ENST00000400163.7 linkuse as main transcript	c.-44-914T>C		intron_variant		5
COL4A1	ENST00000649738.1 linkuse as main transcript	n.212A>G		splice_region_variant, non_coding_transcript_exon_variant	1/31

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.58e-7

AC:

AN:

1319760

Hom.:

Cov.:

AF XY:

0.00000154

AC XY:

AN XY:

649802

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.54e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Brain small vessel disease 1 with or without ocular anomalies

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Porencephalic cyst

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Benign

-0.13

Cadd

Benign

Dann

Benign

0.73

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.028

Eigen_PC

Benign

-0.018

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.33

T;T

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.30

T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

0.34

N;N

MutationTaster

Benign

0.99

N;N;N

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.0

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.94

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.96

P;.

Vest4

0.26

MutPred

0.31

Gain of catalytic residue at G33 (P = 0);Gain of catalytic residue at G33 (P = 0);

MVP

0.73

MPC

0.54

ClinPred

0.48

GERP RS

3.5

Varity_R

0.19

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00078

dbscSNV1_RF

Benign

0.032

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over