2-188998698-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS1

The NM_000090.4(COL3A1):​c.2002C>T​(p.Pro668Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P668T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

COL3A1
NM_000090.4 missense

Scores

1
11
7

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.77
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 -15 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=0.02211824).
BP6
Variant 2-188998698-C-T is Benign according to our data. Variant chr2-188998698-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 199727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188998698-C-T is described in Lovd as [Benign]. Variant chr2-188998698-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00116 (176/152242) while in subpopulation AFR AF= 0.00397 (165/41540). AF 95% confidence interval is 0.00348. There are 0 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL3A1NM_000090.4 linkc.2002C>T p.Pro668Ser missense_variant Exon 29 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.2002C>T p.Pro668Ser missense_variant Exon 29 of 51 1 NM_000090.4 ENSP00000304408.4 P02461-1
COL3A1ENST00000450867.2 linkc.1903C>T p.Pro635Ser missense_variant Exon 28 of 50 1 ENSP00000415346.2 H7C435

Frequencies

GnomAD3 genomes
AF:
0.00115
AC:
175
AN:
152124
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00396
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000322
AC:
81
AN:
251170
Hom.:
0
AF XY:
0.000228
AC XY:
31
AN XY:
135736
show subpopulations
Gnomad AFR exome
AF:
0.00419
Gnomad AMR exome
AF:
0.000231
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000124
AC:
181
AN:
1461638
Hom.:
0
Cov.:
32
AF XY:
0.000118
AC XY:
86
AN XY:
727116
show subpopulations
Gnomad4 AFR exome
AF:
0.00373
Gnomad4 AMR exome
AF:
0.000246
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.000381
GnomAD4 genome
AF:
0.00116
AC:
176
AN:
152242
Hom.:
0
Cov.:
32
AF XY:
0.00109
AC XY:
81
AN XY:
74414
show subpopulations
Gnomad4 AFR
AF:
0.00397
Gnomad4 AMR
AF:
0.000589
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000215
Hom.:
0
Bravo
AF:
0.00147
ESP6500AA
AF:
0.00431
AC:
19
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000445
AC:
54
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
Oct 07, 2021
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 13, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The COL3A1 c.2002C>T (p.Pro668Ser) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 54/120672 control chromosomes at a frequency of 0.0004475, which is approximately 358 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. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign. -

Nov 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

COL3A1: BS1 -

Dec 09, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:3
Oct 19, 2018
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 21, 2023
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 14, 2017
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Ehlers-Danlos syndrome, type 4 Benign:2
Jan 21, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 23, 2024
All of Us Research Program, National Institutes of Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:1
-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.064
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Uncertain
0.010
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.83
D;.
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Uncertain
0.22
D
MetaRNN
Benign
0.022
T;T
MetaSVM
Uncertain
0.61
D
MutationAssessor
Benign
1.8
L;L
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-4.3
D;D
REVEL
Uncertain
0.48
Sift
Benign
0.10
T;T
Sift4G
Benign
0.13
T;T
Polyphen
0.79
P;.
Vest4
0.57
MVP
0.76
MPC
0.63
ClinPred
0.046
T
GERP RS
5.9
Varity_R
0.12
gMVP
0.56

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1801183; hg19: chr2-189863424; API