rs751749989

Positions:

chr13-110307021-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_001845.6(COL4A1):c.7C>A(p.Pro3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000663 in 1,464,626 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00069 ( 1 hom. )

Consequence

COL4A1
NM_001845.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:5

Conservation

PhyloP100: 2.70

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:

COL4A1 (HGNC:):

COL4A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL4A1. . Gene score misZ 3.0194 (greater than the threshold 3.09). Trascript score misZ 4.972 (greater than threshold 3.09). GenCC has associacion of gene with brain small vessel disease 1 with or without ocular anomalies, pontine autosomal dominant microangiopathy with leukoencephalopathy, muscular dystrophy-dystroglycanopathy, type A, microangiopathy and leukoencephalopathy, pontine, autosomal dominant, familial porencephaly, autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome, retinal arterial tortuosity.

BP4

Computational evidence support a benign effect (MetaRNN=0.07972333).

BP6

Variant 13-110307021-G-T is Benign according to our data. Variant chr13-110307021-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289628.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4, Benign=1}. Variant chr13-110307021-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00044 (67/152198) while in subpopulation NFE AF= 0.00078 (53/67980). AF 95% confidence interval is 0.000612. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A1	NM_001845.6 linkuse as main transcript	c.7C>A	p.Pro3Thr	missense_variant	1/52	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2 linkuse as main transcript	c.7C>A	p.Pro3Thr	missense_variant	1/25		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL4A1	ENST00000375820.10 linkuse as main transcript	c.7C>A	p.Pro3Thr	missense_variant	1/52	1	NM_001845.6	ENSP00000364979.4	P02462-1
COL4A1	ENST00000543140.6 linkuse as main transcript	c.7C>A	p.Pro3Thr	missense_variant	1/25	1		ENSP00000443348.1	P02462-2
COL4A2	ENST00000400163.7 linkuse as main transcript	c.-44-839G>T		intron_variant		5		ENSP00000383027.4	A2A352
COL4A1	ENST00000649738.1 linkuse as main transcript	n.137C>A		non_coding_transcript_exon_variant	1/31

Frequencies

GnomAD3 genomes

AF:

0.000441

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000780

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000587

AC:

AN:

80102

Hom.:

AF XY:

0.000568

AC XY:

AN XY:

45798

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000538

Gnomad FIN exome

AF:

0.00144

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.000434

GnomAD4 exome

AF:

0.000689

AC:

904

AN:

1312428

Hom.:

Cov.:

AF XY:

0.000675

AC XY:

436

AN XY:

646298

show subpopulations

Gnomad4 AFR exome

AF:

0.000188

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000630

Gnomad4 FIN exome

AF:

0.00237

Gnomad4 NFE exome

AF:

0.000718

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000440

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.000780

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000794

Hom.:

Bravo

AF:

0.000536

ExAC

AF:

0.000227

AC:

Asia WGS

AF:

0.000580

AC:

AN:

3464

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2024	Reported in an individual with pediatric arterial ischemic stroke in published literature (PMID: 32818659); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32818659) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	COL4A1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -

Brain small vessel disease 1 with or without ocular anomalies

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 26, 2019	This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: BS1,BP4. -

COL4A1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 18, 2024

The COL4A1 c.7C>A variant is predicted to result in the amino acid substitution p.Pro3Thr. This variant was reported as paternally-inherited in an individual with arterial ischemic stroke (Grossi et al. 2020. PubMed ID: 32818659). This variant is reported in 0.11% of alleles in individuals of European (Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Schizencephaly;C0423401:Retinal arterial tortuosity;C2673195:Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome;C3281105:Hemorrhage, intracerebral, susceptibility to;C4551998:Brain small vessel disease 1 with or without ocular anomalies

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Mar 26, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.60

T;T

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.080

T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.34

N;N

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.47

N;N

REVEL

Benign

0.23

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.097

T;T

Polyphen

0.043

B;.

Vest4

0.19

MVP

0.60

MPC

0.43

ClinPred

0.057

GERP RS

1.6

Varity_R

0.092

gMVP

0.56

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

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