rs372220538

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_000393.5(COL5A2):c.3038C>T(p.Ala1013Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000549 in 1,549,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

COL5A2
NM_000393.5 missense, splice_region

Scores

Splicing: ADA: 0.5342

Clinical Significance

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

Conservation

PhyloP100: 4.02

Variant links:

Genes affected

COL5A2 (HGNC:2210): (collagen type V alpha 2 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. Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. [provided by RefSeq, Jul 2008]

COL5A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24092868).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000394 (6/152126) while in subpopulation AFR AF= 0.0000966 (4/41424). AF 95% confidence interval is 0.0000325. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5 link	c.3038C>T	p.Ala1013Val	missense_variant, splice_region_variant	Exon 43 of 54	ENST00000374866.9	NP_000384.2	P05997
COL5A2	XM_011510573.4 link	c.2900C>T	p.Ala967Val	missense_variant, splice_region_variant	Exon 46 of 57		XP_011508875.1
COL5A2	XM_047443251.1 link	c.2900C>T	p.Ala967Val	missense_variant, splice_region_variant	Exon 48 of 59		XP_047299207.1
COL5A2	XM_047443252.1 link	c.2900C>T	p.Ala967Val	missense_variant, splice_region_variant	Exon 47 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9 link	c.3038C>T	p.Ala1013Val	missense_variant, splice_region_variant	Exon 43 of 54	1	NM_000393.5	ENSP00000364000.3		P05997
COL5A2	ENST00000618828.1 link	c.1877C>T	p.Ala626Val	missense_variant, splice_region_variant	Exon 36 of 47	5		ENSP00000482184.1		A0A087WYX9

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000320

AC:

AN:

156464

Hom.:

AF XY:

0.00

AC XY:

AN XY:

82340

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000404

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000265

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000165

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000565

AC:

AN:

1397354

Hom.:

Cov.:

AF XY:

0.0000435

AC XY:

AN XY:

689388

show subpopulations

Gnomad4 AFR exome

AF:

0.000158

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000140

Gnomad4 SAS exome

AF:

0.0000505

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000585

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000966

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.000479

AC:

ESP6500EA

AF:

0.000124

AC:

ExAC

AF:

0.0000368

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Mar 09, 2022

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; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Nov 13, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

One variant of uncertain clinical significance, c.3038C>T; p.Ala1013Val, was detected in the COL5A2 gene by massively parallel sequencing and confirmed by Sanger sequencing. The p.Ala1013Val (rs372220538) is listed in the Exome Aggregation Consortium Browser with an overall allele frequency of 0.01 percent (identified in 2 out of 20,648 chromosomes) and with frequency of 0.07 percent (identified in 2 out of 2726 chromosomes) in African populations. This variant has not been previously reported in the scientific literature or gene-specific variant databases. We have previously identified this variant in an individual with subtle skeletal findings who also carried pathogenic variant in the SMAD3 gene. The alanine 1013 is highly conserved up to Xenopus tropicalis but computational prediction programs do not agree in assessing the effect of this variant (SIFT: tolerated, PolyPhen-2: benign, and MutationTaster: disease causing). p.Ala1013Val is not located in the triple helix domain and computational splice prediction programs do not suggest significant effect on splicing (Alamut software v.2.7.1).. Altogether, there is not enough information to classify this variant with certainty. Pathogenic COL5A2 variants are associated with Ehlers-Danlos syndrome, type I (MIM:130000). -

Mar 14, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Dec 11, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A1013V variant (also known as c.3038C>T), located in coding exon 43 of the COL5A2 gene, results from a C to T substitution at nucleotide position 3038. The alanine at codon 1013 is replaced by valine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Ehlers-Danlos syndrome, classic type, 1

Uncertain:1

Oct 13, 2022

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 valine, which is neutral and non-polar, at codon 1013 of the COL5A2 protein (p.Ala1013Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with COL5A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 576774). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C55"). 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

0.12

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;T;T

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.86

.;D;D

M_CAP

Benign

0.072

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

1.5

L;.;L

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.4

N;.;.

REVEL

Uncertain

0.33

Sift

Benign

0.47

T;.;.

Sift4G

Benign

0.27

T;T;.

Polyphen

0.92

P;.;P

Vest4

0.33

MVP

0.72

MPC

0.26

ClinPred

0.096

GERP RS

5.1

Varity_R

0.028

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.53

dbscSNV1_RF

Benign

0.46

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