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

1
17

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2
Missense variant in the COL3A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 495 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 4.0879 (above the threshold of 3.09). Trascript score misZ: 4.5995 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank MANE Protein UniProt
COL3A1NM_000090.4 linkc.4059T>G p.His1353Gln missense_variant Exon 50 of 51 ENST00000304636.9 NP_000081.2 P02461-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL3A1ENST00000304636.9 linkc.4059T>G p.His1353Gln missense_variant Exon 50 of 51 1 NM_000090.4 ENSP00000304408.4 P02461-1
COL3A1ENST00000450867.2 linkc.3960T>G p.His1320Gln missense_variant Exon 49 of 50 1 ENSP00000415346.2 H7C435
COL3A1ENST00000487010.1 linkn.1438T>G non_coding_transcript_exon_variant Exon 2 of 3 2

Frequencies

GnomAD3 genomes
AF:
0.996
AC:
151524
AN:
152196
Hom.:
75430
Cov.:
32
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.:
54
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.:
32
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
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 02, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jan 05, 2017
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, type 4 Benign:4
Jul 22, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 03, 2024
All of Us Research Program, National Institutes of Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:2
Nov 19, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 05, 2018
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:2
Nov 27, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome Benign:1
Jul 22, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.044
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
14
DANN
Benign
0.39
DEOGEN2
Benign
0.22
T;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.17
N
LIST_S2
Benign
0.22
T;T
MetaRNN
Benign
8.1e-7
T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
-3.7
N;.
PrimateAI
Uncertain
0.58
T
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
T
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.

Other links and lift over

dbSNP: rs1516446; hg19: chr2-189875421; API