chr2-189006384-G-A

Position:

chr2-189006384-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBP6BS1

The ENST00000304636.9(COL3A1):c.3133G>A(p.Ala1045Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000284 in 1,614,126 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1045V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

COL3A1
ENST00000304636.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:16

Conservation

PhyloP100: 1.47

Variant links:

Genes affected

COL3A1 (HGNC:2201): (collagen type III alpha 1 chain) This gene encodes the pro-alpha1 chains of type III collagen, a fibrillar collagen that is found in extensible connective tissues such as skin, lung, uterus, intestine and the vascular system, frequently in association with type I collagen. Mutations in this gene are associated with Ehlers-Danlos syndrome type IV, and with aortic and arterial aneurysms. [provided by R. Dalgleish, Feb 2008]

COL3A1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000304636.9

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL3A1. . Gene score misZ 4.0879 (greater than the threshold 3.09). Trascript score misZ 4.5995 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, vascular type, autosomal dominant Ehlers-Danlos syndrome, vascular type, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.014062673).

BP6

Variant 2-189006384-G-A is Benign according to our data. Variant chr2-189006384-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197477.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1, Likely_benign=7}. Variant chr2-189006384-G-A is described in Lovd as [Likely_benign]. Variant chr2-189006384-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000368 (56/152244) while in subpopulation EAS AF= 0.00618 (32/5174). AF 95% confidence interval is 0.0045. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL3A1	NM_000090.4 linkuse as main transcript	c.3133G>A	p.Ala1045Thr	missense_variant	43/51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9 linkuse as main transcript	c.3133G>A	p.Ala1045Thr	missense_variant	43/51	1	NM_000090.4	ENSP00000304408	P1	P02461-1
COL3A1	ENST00000450867.2 linkuse as main transcript	c.3034G>A	p.Ala1012Thr	missense_variant	42/50	1		ENSP00000415346

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00617

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000573

AC:

144

AN:

251364

Hom.:

AF XY:

0.000574

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00533

Gnomad SAS exome

AF:

0.000947

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000276

AC:

403

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000307

AC XY:

223

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00486

Gnomad4 SAS exome

AF:

0.000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000755

Gnomad4 OTH exome

AF:

0.000944

GnomAD4 genome

AF:

0.000368

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00618

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000313

Hom.:

Bravo

AF:

0.000510

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000585

AC:

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:16

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.5% (46/8636) East Asian; ClinVar: 1 VUS, 1 LB; Path for nonsense at same codon -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 06, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2020	This variant is associated with the following publications: (PMID: 22001912, 25834947, 30115950, 27888582, 32123317) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 12, 2017	Variant summary: The COL3A1 c.3133G>A (p.Ala1045Thr) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome. However, these predictions have yet to be functionally assessed. This variant was found in 71/121484 control chromosomes at a frequency of 0.0005844, which is approximately 468 times the estimated maximal expected allele frequency of a pathogenic COL3A1 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories classified this variant as likely benign/benign. Taken together, this variant is classified as benign. -

Ehlers-Danlos syndrome, type 4

Benign:4

Likely benign, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Dec 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 13, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 13, 2019	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. -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 09, 2018	- -

Ehlers-Danlos syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 23, 2021

- -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.66

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.014

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

1.1

MutationTaster

Benign

0.78

D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.34

Sift

Benign

0.086

Sift4G

Benign

0.26

Polyphen

0.99

Vest4

0.42

MVP

0.82

MPC

1.2

ClinPred

0.034

GERP RS

2.3

Varity_R

0.045

gMVP

0.18

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