rs863223451

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP6

The NM_000093.5(COL5A1):c.3868G>A(p.Ala1290Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,550,966 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1290G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.705

Variant links:

Genes affected

COL5A1 (HGNC:2209): (collagen type V alpha 1 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. The encoded procollagen protein occurs commonly as the heterotrimer pro-alpha1(V)-pro-alpha1(V)-pro-alpha2(V). Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

COL5A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP2

Missense variant where missense usually causes diseases, COL5A1

BP6

Variant 9-134813998-G-A is Benign according to our data. Variant chr9-134813998-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212967.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL5A1	NM_000093.5 linkuse as main transcript	c.3868G>A	p.Ala1290Thr	missense_variant	49/66	ENST00000371817.8
COL5A1	NM_001278074.1 linkuse as main transcript	c.3868G>A	p.Ala1290Thr	missense_variant	49/66
COL5A1	XM_017014266.3 linkuse as main transcript	c.3868G>A	p.Ala1290Thr	missense_variant	49/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8 linkuse as main transcript	c.3868G>A	p.Ala1290Thr	missense_variant	49/66	1	NM_000093.5	P4	P20908-1
COL5A1	ENST00000371820.4 linkuse as main transcript	c.3868G>A	p.Ala1290Thr	missense_variant	49/66	2		A2	P20908-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000193

AC:

AN:

155416

Hom.:

AF XY:

0.00

AC XY:

AN XY:

82232

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000404

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:

0.0000334

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1398744

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

689956

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000559

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000559

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000148

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2015

The p.A1290T variant (also known as c.3868G>A), located in coding exon 49 of the COL5A1 gene, results from a G to A substitution at nucleotide position 3868. The alanine at codon 1290 is replaced by threonine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6049 samples (12098 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 13, 2014

The A1290T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A1290T variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A1290T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. Moreover, a missense mutations in a nearby residue (E1292K) has been reported in association with EDS, supporting the functional importance of this region of the protein. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available clinical and molecular information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.This variant was found in COL5A1,TAAD -

Ehlers-Danlos syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 20, 2022

- -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.37

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.85

D;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.38

T;T

MetaSVM

Benign

-0.29

MutationAssessor

Benign

0.73

N;N

MutationTaster

Benign

0.77

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.1

N;.

REVEL

Benign

0.28

Sift

Benign

0.17

T;.

Sift4G

Benign

0.28

T;T

Polyphen

0.0010

B;.

Vest4

0.27

MutPred

0.31

Gain of phosphorylation at A1290 (P = 0.0033);Gain of phosphorylation at A1290 (P = 0.0033);

MVP

0.59

MPC

0.29

ClinPred

0.16

GERP RS

4.7

Varity_R

0.056

gMVP

0.064

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.24

Position offset: 3

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