9-134818732-C-T

Position:

chr9-134818732-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2

The NM_000093.5(COL5A1):c.4307C>T(p.Pro1436Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000862 in 1,611,614 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 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.79

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 -2 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, 0.802

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5 linkuse as main transcript	c.4307C>T	p.Pro1436Leu	missense_variant	55/66	ENST00000371817.8	NP_000084.3	P20908-1A0A024R8E5B2ZZ86Q59EE7
COL5A1	NM_001278074.1 linkuse as main transcript	c.4307C>T	p.Pro1436Leu	missense_variant	55/66		NP_001265003.1	B2ZZ86Q59EE7
COL5A1	XM_017014266.3 linkuse as main transcript	c.4307C>T	p.Pro1436Leu	missense_variant	55/65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 linkuse as main transcript	c.4307C>T	p.Pro1436Leu	missense_variant	55/66	1	NM_000093.5	ENSP00000360882.3		P20908-1
COL5A1	ENST00000371820.4 linkuse as main transcript	c.4307C>T	p.Pro1436Leu	missense_variant	55/66	2		ENSP00000360885.4		P20908-2H7BY82

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

151990

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000245

AC:

AN:

244540

Hom.:

AF XY:

0.0000300

AC XY:

AN XY:

133272

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:

0.0000456

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000877

AC:

128

AN:

1459624

Hom.:

Cov.:

AF XY:

0.0000923

AC XY:

AN XY:

726048

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000107

Gnomad4 OTH exome

AF:

0.0000995

GnomAD4 genome

AF:

0.0000724

AC:

AN:

151990

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.0000725

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000100

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

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

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 03, 2023

The p.P1436L variant (also known as c.4307C>T), located in coding exon 55 of the COL5A1 gene, results from a C to T substitution at nucleotide position 4307. The proline at codon 1436 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in a subject with internal carotid artery dissection (Härtl J et al. J Neurol, 2023 Mar;270:1501-1511). 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 29, 2024

Identified in a patient with ischemic stroke and internal carotid artery dissection (PMID: 36411388); Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (PMID: 22696272; HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22696272, 36411388) -

Ehlers-Danlos syndrome, classic type, 1;C5543412:Fibromuscular dysplasia, multifocal

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 15, 2021

- -

Connective tissue disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

- -

Ehlers-Danlos syndrome, classic type

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 10-21-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Benign

0.82

DEOGEN2

Uncertain

0.70

D;.

Eigen

Benign

0.050

Eigen_PC

Benign

0.028

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Benign

1.2

L;L

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.8

D;.

REVEL

Uncertain

0.58

Sift

Benign

0.17

T;.

Sift4G

Benign

0.18

T;T

Polyphen

0.92

P;.

Vest4

0.61

MVP

0.77

MPC

0.30

ClinPred

0.32

GERP RS

4.9

Varity_R

0.17

gMVP

0.30

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