9-134824654-C-T

Position:

chr9-134824654-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2

The NM_000093.5(COL5A1):c.4753C>T(p.Arg1585Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,614,180 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).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.291

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:

COL5A1 (HGNC:):

COL5A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 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, 0.922

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5 linkuse as main transcript	c.4753C>T	p.Arg1585Trp	missense_variant	62/66	ENST00000371817.8	NP_000084.3	P20908-1A0A024R8E5B2ZZ86Q59EE7
COL5A1	NM_001278074.1 linkuse as main transcript	c.4753C>T	p.Arg1585Trp	missense_variant	62/66		NP_001265003.1	B2ZZ86Q59EE7
COL5A1	XM_017014266.3 linkuse as main transcript	c.4753C>T	p.Arg1585Trp	missense_variant	62/65		XP_016869755.1
LOC101448202	NR_103451.2 linkuse as main transcript	n.71-4445G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL5A1	ENST00000371817.8 linkuse as main transcript	c.4753C>T	p.Arg1585Trp	missense_variant	62/66	1	NM_000093.5	ENSP00000360882.3	P20908-1
COL5A1	ENST00000371820.4 linkuse as main transcript	c.4753C>T	p.Arg1585Trp	missense_variant	62/66	2		ENSP00000360885.4	P20908-2H7BY82
COL5A1	ENST00000460264.5 linkuse as main transcript	n.221C>T		non_coding_transcript_exon_variant	3/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000399

AC:

AN:

250668

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000576

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 04, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Not located in the triple helical region, where the majority of pathogenic missense variants occur (PMID: 22696272; HGMD); This variant is associated with the following publications: (PMID: 22696272) -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2024

The p.R1585W variant (also known as c.4753C>T), located in coding exon 62 of the COL5A1 gene, results from a C to T substitution at nucleotide position 4753. The arginine at codon 1585 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Ehlers-Danlos syndrome, classic type

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 15, 2018

The COL5A1 c.4753C>T; p.Arg1585Trp variant (rs546865410), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 212988). This variant is found in the general population with an overall allele frequency of 0.004% (11/282004 alleles) in the Genome Aggregation Database. The arginine at codon 1585 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Arg1585Trp variant is uncertain at this time. -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

D;.

Eigen

Benign

0.0051

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.61

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Uncertain

0.76

MutationAssessor

Pathogenic

3.3

M;M

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.2

D;.

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.91

MVP

0.76

MPC

0.31

ClinPred

0.96

GERP RS

-2.2

Varity_R

0.57

gMVP

0.86

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