chr2-189006943-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1PP2

The NM_000090.4(COL3A1):c.3208G>T(p.Ala1070Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,612,968 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1070G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

COL3A1
NM_000090.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.0700

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant Ehlers-Danlos syndrome, vascular type
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
Ehlers-Danlos syndrome, vascular type
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
polymicrogyria with or without vascular-type Ehlers-Danlos syndrome
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

COL3A1 links:

ENSG00000295704 (HGNC:):

ENSG00000295704 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000090.4

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, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome, autosomal dominant Ehlers-Danlos syndrome, vascular type.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4 link	c.3208G>T	p.Ala1070Ser	missense_variant	Exon 44 of 51	ENST00000304636.9	NP_000081.2	P02461-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9 link	c.3208G>T	p.Ala1070Ser	missense_variant	Exon 44 of 51	1	NM_000090.4	ENSP00000304408.4		P02461-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151804

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461164

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

726882

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5596

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1111676

Other (OTH)

AF:

0.0000331

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151804

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74108

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41358

American (AMR)

AF:

0.00

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67932

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, type 4

Uncertain:2

Dec 13, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces alanine with serine at codon 1070 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individual(s) with clinical features of COL3A1-related conditions (ClinVar SCV000756054.2). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1070 of the COL3A1 protein (p.Ala1070Ser). This variant is present in population databases (rs376738516, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of COL3A1-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 529320). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Ehlers-Danlos syndrome, type 4;C5193040:Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome

Uncertain:1

Mar 15, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Mar 06, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ehlers-Danlos syndrome, dominant type 4

Uncertain:1

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with COL3A1-related disease. Missense variants affecting glycine residues within the collagen triple helical region exert a dominant negative effect, while null alleles result in haploinsufficiency which may confer delayed onset and a milder clinical course (PMID: 21637106; 29346445). (I) 0108 - This gene is associated with both recessive and dominant disease. Vascular Ehlers-Danlos syndrome (EDS), AD; Polymicrogyria with or without vascular EDS, AR (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated triple helical region but does not affect a glycine residue (Decipher). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a variant of uncertain significance (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.53

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.86

PhyloP100

0.070

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.46

REVEL

Benign

0.22

Sift

Benign

0.59

Sift4G

Benign

0.77

Polyphen

0.38

Vest4

0.22

MVP

0.72

MPC

1.2

ClinPred

0.19

GERP RS

3.1

Varity_R

0.065

gMVP

0.20

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over