rs201880122

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS1

The NM_000090.4(COL3A1):c.3413C>T(p.Pro1138Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

COL3A1
NM_000090.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3

Conservation

PhyloP100: 0.750

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 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.

BP6

Variant 2-189007934-C-T is Benign according to our data. Variant chr2-189007934-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 404306.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=5}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000131 (20/152098) while in subpopulation NFE AF= 0.000279 (19/68030). AF 95% confidence interval is 0.000182. There are 0 homozygotes in gnomad4. There are 7 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
COL3A1	NM_000090.4 link	c.3413C>T	p.Pro1138Leu	missense_variant	Exon 46 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.3413C>T	p.Pro1138Leu	missense_variant	Exon 46 of 51	1	NM_000090.4	ENSP00000304408.4		P02461-1
COL3A1	ENST00000450867.2 link	c.3314C>T	p.Pro1105Leu	missense_variant	Exon 45 of 50	1		ENSP00000415346.2		H7C435

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000279

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000131

AC:

AN:

251428

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000136

AC:

199

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

108

AN XY:

727238

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:

0.000168

Gnomad4 NFE exome

AF:

0.000159

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000131

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000161

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:2Benign:1

Jan 23, 2024

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Jan 18, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with leucine at codon 1138 of the COL3A1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 55/282810 chromosomes 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. -

Jan 03, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, type 4

Uncertain:1Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided

Uncertain:2

Aug 26, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

Dec 28, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (HGMD) -

COL3A1-related disorder

Uncertain:1

Jun 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The COL3A1 c.3413C>T variant is predicted to result in the amino acid substitution p.Pro1138Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.58

MetaSVM

Uncertain

0.57

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-7.5

REVEL

Uncertain

0.54

Sift

Uncertain

0.0020

Sift4G

Benign

0.14

Polyphen

0.90

Vest4

0.47

MVP

0.66

MPC

0.21

ClinPred

0.38

GERP RS

5.5

Varity_R

0.70

gMVP

0.42

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over