rs749543804

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_000090.4(COL3A1):​c.3629G>A​(p.Gly1210Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

COL3A1
NM_000090.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.345
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 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=0.08224058).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL3A1NM_000090.4 linkuse as main transcriptc.3629G>A p.Gly1210Asp missense_variant 48/51 ENST00000304636.9 NP_000081.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL3A1ENST00000304636.9 linkuse as main transcriptc.3629G>A p.Gly1210Asp missense_variant 48/511 NM_000090.4 ENSP00000304408 P1P02461-1
COL3A1ENST00000450867.2 linkuse as main transcriptc.3530G>A p.Gly1177Asp missense_variant 47/501 ENSP00000415346
COL3A1ENST00000487010.1 linkuse as main transcriptn.726G>A non_coding_transcript_exon_variant 1/32

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152206
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000294
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251392
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135856
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461888
Hom.:
0
Cov.:
30
AF XY:
0.00000550
AC XY:
4
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
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:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152206
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenOct 01, 2019- -
Ehlers-Danlos syndrome, type 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 27, 2023This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1210 of the COL3A1 protein (p.Gly1210Asp). This variant is present in population databases (rs749543804, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 529324). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL3A1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.31
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
12
DANN
Benign
0.68
DEOGEN2
Uncertain
0.46
T;.
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.61
T;T
M_CAP
Benign
0.049
D
MetaRNN
Benign
0.082
T;T
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
1.4
L;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-1.6
N;D
REVEL
Benign
0.24
Sift
Benign
0.25
T;T
Sift4G
Benign
0.31
T;T
Polyphen
0.18
B;.
Vest4
0.14
MutPred
0.46
Loss of methylation at K1212 (P = 0.0839);.;
MVP
0.60
MPC
0.27
ClinPred
0.041
T
GERP RS
-0.95
Varity_R
0.18
gMVP
0.93

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: rs749543804; hg19: chr2-189873753; API