chr9-134730363-C-A

Position:

chr9-134730363-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP3BP6BS2

The NM_000093.5(COL5A1):c.1052C>A(p.Pro351Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P351L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.86

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 Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL5A1. . Gene score misZ 2.0682 (greater than the threshold 3.09). Trascript score misZ 4.1823 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, classic type, 1, arterial disorder, Ehlers-Danlos syndrome, classic type.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.761

BP6

Variant 9-134730363-C-A is Benign according to our data. Variant chr9-134730363-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 575918.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BS2

High AC in GnomAdExome4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL5A1	NM_000093.5 linkuse as main transcript	c.1052C>A	p.Pro351Gln	missense_variant	7/66	ENST00000371817.8
COL5A1	NM_001278074.1 linkuse as main transcript	c.1052C>A	p.Pro351Gln	missense_variant	7/66
COL5A1	XM_017014266.3 linkuse as main transcript	c.1052C>A	p.Pro351Gln	missense_variant	7/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8 linkuse as main transcript	c.1052C>A	p.Pro351Gln	missense_variant	7/66	1	NM_000093.5	P4	P20908-1
COL5A1	ENST00000371820.4 linkuse as main transcript	c.1052C>A	p.Pro351Gln	missense_variant	7/66	2		A2	P20908-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152220

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251418

Hom.:

AF XY:

0.0000221

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:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727234

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:

0.0000405

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, classic type, 1

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 05, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 17, 2023	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 27, 2023

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; Not located in the triple helical region, where the majority of pathogenic missense variants occur (Symoens et al., 2012; HGMD); This variant is associated with the following publications: (PMID: 22696272) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.13

T;.

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.78

T;T

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Uncertain

2.5

M;M

MutationTaster

Benign

0.96

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.3

N;.

REVEL

Uncertain

0.36

Sift

Benign

0.032

D;.

Sift4G

Benign

0.087

T;T

Polyphen

1.0

D;.

Vest4

0.69

MutPred

0.29

Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);

MVP

0.75

MPC

0.61

ClinPred

0.34

GERP RS

4.5

Varity_R

0.088

gMVP

0.26

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