chr2-188994274-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_000090.4(COL3A1):​c.1235C>T​(p.Ala412Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A412S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

COL3A1
NM_000090.4 missense

Scores

12
7

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 2.67
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 Uncertain_significance. Variant got 5 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000090.4
PM2
Very rare variant in population databases, with high coverage;
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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL3A1NM_000090.4 linkc.1235C>T p.Ala412Val missense_variant Exon 18 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.1235C>T p.Ala412Val missense_variant Exon 18 of 51 1 NM_000090.4 ENSP00000304408.4 P02461-1
COL3A1ENST00000450867.2 linkc.1136C>T p.Ala379Val missense_variant Exon 17 of 50 1 ENSP00000415346.2 H7C435

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461654
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727146
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Uncertain:1
Mar 30, 2016
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.069
D
BayesDel_noAF
Benign
-0.14
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.71
D;.
Eigen
Benign
0.086
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Uncertain
0.086
D
MetaRNN
Uncertain
0.56
D;D
MetaSVM
Uncertain
0.39
D
MutationAssessor
Benign
0.88
L;L
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.9
N;N
REVEL
Uncertain
0.30
Sift
Uncertain
0.0040
D;T
Sift4G
Uncertain
0.045
D;D
Polyphen
0.31
B;.
Vest4
0.59
MutPred
0.51
Gain of catalytic residue at A412 (P = 0.1152);Gain of catalytic residue at A412 (P = 0.1152);
MVP
0.77
MPC
0.63
ClinPred
0.84
D
GERP RS
5.6
Varity_R
0.22
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.

Other links and lift over

dbSNP: rs1057519250; hg19: chr2-189859000; API