rs1516446

Positions:

chr2-189010695-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000090.4(COL3A1):c.4059T>G(p.His1353Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,614,158 control chromosomes in the GnomAD database, including 805,640 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 1.0 ( 75488 hom., cov: 32)

Exomes 𝑓: 1.0 ( 730152 hom. )

Consequence

COL3A1
NM_000090.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.72

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:

COL3A1 (HGNC:):

COL3A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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=8.1083687E-7).

BP6

Variant 2-189010695-T-G is Benign according to our data. Variant chr2-189010695-T-G is described in ClinVar as [Benign]. Clinvar id is 226540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL3A1	NM_000090.4 linkuse as main transcript	c.4059T>G	p.His1353Gln	missense_variant	50/51	ENST00000304636.9	NP_000081.2	P02461-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL3A1	ENST00000304636.9 linkuse as main transcript	c.4059T>G	p.His1353Gln	missense_variant	50/51	1	NM_000090.4	ENSP00000304408.4	P02461-1
COL3A1	ENST00000450867.2 linkuse as main transcript	c.3960T>G	p.His1320Gln	missense_variant	49/50	1		ENSP00000415346.2	H7C435
COL3A1	ENST00000487010.1 linkuse as main transcript	n.1438T>G		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

AF:

0.996

AC:

151524

AN:

152196

Hom.:

75430

Cov.:

show subpopulations

Gnomad AFR

AF:

0.985

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.999

Gnomad ASJ

AF:

0.997

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.998

GnomAD3 exomes

AF:

0.999

AC:

250991

AN:

251310

Hom.:

125341

AF XY:

0.999

AC XY:

135669

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.985

Gnomad AMR exome

AF:

0.999

Gnomad ASJ exome

AF:

0.996

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.999

GnomAD4 exome

AF:

0.999

AC:

1461064

AN:

1461844

Hom.:

730152

Cov.:

AF XY:

1.00

AC XY:

726861

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.985

Gnomad4 AMR exome

AF:

0.999

Gnomad4 ASJ exome

AF:

0.996

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

1.00

Gnomad4 FIN exome

AF:

1.00

Gnomad4 NFE exome

AF:

1.00

Gnomad4 OTH exome

AF:

0.999

GnomAD4 genome

AF:

0.996

AC:

151641

AN:

152314

Hom.:

75488

Cov.:

AF XY:

0.996

AC XY:

74169

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.985

Gnomad4 AMR

AF:

0.999

Gnomad4 ASJ

AF:

0.997

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

1.00

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

1.00

Gnomad4 OTH

AF:

0.998

Alfa

AF:

0.999

Hom.:

151700

Bravo

AF:

0.995

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.985

AC:

4340

ESP6500EA

AF:

1.00

AC:

8600

ExAC

AF:

0.999

AC:

121231

Asia WGS

AF:

0.999

AC:

3475

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 02, 2014	This is a RefSeq error. The reference base (c.4059T) is the minor allele. This a llele (T) has been identified in 1.5% (66/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1516446) and thus meets criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 05, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Ehlers-Danlos syndrome, type 4

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 03, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.39

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.22

T;T

MetaRNN

Benign

8.1e-7

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-3.7

N;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

4.7

N;N

REVEL

Benign

0.20

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.19

MutPred

0.73

Loss of helix (P = 0.028);.;

MPC

0.21

ClinPred

0.00099

GERP RS

1.4

Varity_R

0.068

gMVP

0.51

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