rs768348357

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_000393.5(COL5A2):c.1621G>T(p.Ala541Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000509 in 1,610,208 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).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

COL5A2
NM_000393.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1O:1

Conservation

PhyloP100: 3.80

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3480484).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000555 (81/1458174) while in subpopulation NFE AF= 0.0000695 (77/1108676). AF 95% confidence interval is 0.0000564. There are 0 homozygotes in gnomad4_exome. There are 37 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 81 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5 link	c.1621G>T	p.Ala541Ser	missense_variant	25/54	ENST00000374866.9	NP_000384.2	P05997
COL5A2	XM_011510573.4 link	c.1483G>T	p.Ala495Ser	missense_variant	28/57		XP_011508875.1
COL5A2	XM_047443251.1 link	c.1483G>T	p.Ala495Ser	missense_variant	30/59		XP_047299207.1
COL5A2	XM_047443252.1 link	c.1483G>T	p.Ala495Ser	missense_variant	29/58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9 link	c.1621G>T	p.Ala541Ser	missense_variant	25/54	1	NM_000393.5	ENSP00000364000.3		P05997
COL5A2	ENST00000618828.1 link	c.460G>T	p.Ala154Ser	missense_variant	18/47	5		ENSP00000482184.1		A0A087WYX9

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152034

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:

0.0000239

AC:

AN:

251056

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135740

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:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000555

AC:

AN:

1458174

Hom.:

Cov.:

AF XY:

0.0000510

AC XY:

AN XY:

725744

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.0000695

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152034

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74252

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

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, classic type, 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 22, 2023	The COL5A2 c.1621G>T; p.Ala541Ser variant (rs768348357), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 213098). This variant is found in the non-Finnish European population with an allele frequency of 0.0053% (6/113,524 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.339). Due to limited information, the clinical significance of this variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 13, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2016

The p.A541S variant (also known as c.1621G>T), located in coding exon 25 of the COL5A2 gene, results from a G to T substitution at nucleotide position 1621. The alanine at codon 541 is replaced by serine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs768348357. Based on data from ExAC, the T allele was reported in 3 of 119932 (0.002%) total alleles (Exome Aggregation Consortium (ExAC), Cambridge, MA (URL: http://exac.broadinstitute.org) [Accessed March 30, 2016]). This variant was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 11, 2022

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 213098; ClinVar) -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2023

- -

Ehlers-Danlos syndrome, classic type

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpretted as Uncertain significance and reported on 11/10/2015 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;T;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.82

.;T;T

M_CAP

Benign

0.062

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Uncertain

0.34

MutationAssessor

Benign

0.48

N;.;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.88

N;.;.

REVEL

Uncertain

0.34

Sift

Benign

0.31

T;.;.

Sift4G

Benign

0.95

T;T;.

Polyphen

0.95

P;.;P

Vest4

0.43

MutPred

0.28

Gain of phosphorylation at A541 (P = 0.0069);.;Gain of phosphorylation at A541 (P = 0.0069);

MVP

0.77

MPC

0.44

ClinPred

0.35

GERP RS

5.6

Varity_R

0.085

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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