rs377488010

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The NM_000093.5(COL5A1):c.1303C>G(p.Pro435Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000104 in 1,613,810 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P435L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

COL5A1
NM_000093.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2O:1

Conservation

PhyloP100: 4.63

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 -5 ACMG points.

PP2

Missense variant where missense usually causes diseases, COL5A1

BP4

Computational evidence support a benign effect (MetaRNN=0.41052788).

BP6

Variant 9-134731634-C-G is Benign according to our data. Variant chr9-134731634-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213021.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=1, Benign=1, not_provided=1}.

BS2

High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL5A1	NM_000093.5 linkuse as main transcript	c.1303C>G	p.Pro435Ala	missense_variant	8/66	ENST00000371817.8
COL5A1	NM_001278074.1 linkuse as main transcript	c.1303C>G	p.Pro435Ala	missense_variant	8/66
COL5A1	XM_017014266.3 linkuse as main transcript	c.1303C>G	p.Pro435Ala	missense_variant	8/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8 linkuse as main transcript	c.1303C>G	p.Pro435Ala	missense_variant	8/66	1	NM_000093.5	P4	P20908-1
COL5A1	ENST00000371820.4 linkuse as main transcript	c.1303C>G	p.Pro435Ala	missense_variant	8/66	2		A2	P20908-2
COL5A1	ENST00000469093.1 linkuse as main transcript	n.42C>G		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000563

AC:

AN:

248628

Hom.:

AF XY:

0.0000520

AC XY:

AN XY:

134630

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:

0.000126

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000106

AC:

155

AN:

1461618

Hom.:

Cov.:

AF XY:

0.0000976

AC XY:

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000135

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000185

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2022	Reported in an individual with a clinical diagnosis of Ehlers-Danlos syndrome (Dupuis et al., 2012), an individual with multifocal fibromuscular dysplasia (mFMD) (Richer et al., 2019), and an individual who underwent screening for bleeding, thrombotic and/or platelet disorders (Downes et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on 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: 32938213, 31064749) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	The COL5A1 c.1303C>G; p.Pro435Ala variant (rs377488010) is reported in the literature in an individual affected with fibromuscular dysplasia (Georges 2022), and in an individual tested for bleeding, thrombotic, and/or platelet disorders (Downes 2019). This variant is reported in ClinVar (Variation ID: 213021), and is found in the non-Finnish European population with an allele frequency of 0.015% (20/126,666 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.466). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Downes K et al. Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders. Blood. 2019 Dec 5;134(23):2082-2091. PMID: 31064749. Georges A et al. The complex genetic basis of fibromuscular dysplasia, a systemic arteriopathy associated with multiple forms of cardiovascular disease. Clin Sci (Lond). 2022 Aug 31;136(16):1241-1255. PMID: 36043395. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The p.P435A variant (also known as c.1303C>G), located in coding exon 8 of the COL5A1 gene, results from a C to G substitution at nucleotide position 1303. The proline at codon 435 is replaced by alanine, an amino acid with highly similar properties. This alteration has been reported in a fibromuscular dysplasia cohort (Richer J et al. Arterioscler Thromb Vasc Biol, 2020 11;40:2686-2699). 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. -

Abnormal bleeding

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Ehlers-Danlos syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 06, 2022

- -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Ehlers-Danlos syndrome, classic type

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

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

0.15

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.11

Cadd

Benign

Dann

Benign

0.95

DEOGEN2

Benign

0.22

T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.074

MetaRNN

Benign

0.41

T;T

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.9

D;.

REVEL

Uncertain

0.47

Sift

Benign

0.066

T;.

Sift4G

Benign

0.13

T;T

Polyphen

0.99

D;.

Vest4

0.58

MVP

0.70

MPC

0.63

ClinPred

0.28

GERP RS

4.1

Varity_R

0.067

gMVP

0.64

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