rs7551175

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000196061.5(PLOD1):c.295G>A(p.Ala99Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,613,404 control chromosomes in the GnomAD database, including 31,170 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A99A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.26 ( 7504 hom., cov: 32)

Exomes 𝑓: 0.17 ( 23666 hom. )

Consequence

PLOD1
ENST00000196061.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.26

Variant links:

Genes affected

PLOD1 (HGNC:9081): (procollagen-lysine,2-oxoglutarate 5-dioxygenase 1) Lysyl hydroxylase is a membrane-bound homodimeric protein localized to the cisternae of the endoplasmic reticulum. The enzyme (cofactors iron and ascorbate) catalyzes the hydroxylation of lysyl residues in collagen-like peptides. The resultant hydroxylysyl groups are attachment sites for carbohydrates in collagen and thus are critical for the stability of intermolecular crosslinks. Some patients with Ehlers-Danlos syndrome type VI have deficiencies in lysyl hydroxylase activity. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PLOD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.0392534E-4).

BP6

Variant 1-11949899-G-A is Benign according to our data. Variant chr1-11949899-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 196247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11949899-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLOD1	NM_000302.4 linkuse as main transcript	c.295G>A	p.Ala99Thr	missense_variant	3/19	ENST00000196061.5	NP_000293.2
PLOD1	NM_001316320.2 linkuse as main transcript	c.436G>A	p.Ala146Thr	missense_variant	4/20		NP_001303249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5 linkuse as main transcript	c.295G>A	p.Ala99Thr	missense_variant	3/19	1	NM_000302.4	ENSP00000196061	P1	Q02809-1

Frequencies

GnomAD3 genomes

AF:

0.259

AC:

39354

AN:

151932

Hom.:

7475

Cov.:

show subpopulations

Gnomad AFR

AF:

0.540

Gnomad AMI

AF:

0.151

Gnomad AMR

AF:

0.142

Gnomad ASJ

AF:

0.129

Gnomad EAS

AF:

0.255

Gnomad SAS

AF:

0.214

Gnomad FIN

AF:

0.114

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.150

Gnomad OTH

AF:

0.231

GnomAD3 exomes

AF:

0.181

AC:

45490

AN:

251356

Hom.:

5642

AF XY:

0.176

AC XY:

23952

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.550

Gnomad AMR exome

AF:

0.0894

Gnomad ASJ exome

AF:

0.145

Gnomad EAS exome

AF:

0.253

Gnomad SAS exome

AF:

0.213

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.153

Gnomad OTH exome

AF:

0.155

GnomAD4 exome

AF:

0.167

AC:

243327

AN:

1461354

Hom.:

23666

Cov.:

AF XY:

0.166

AC XY:

120609

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.546

Gnomad4 AMR exome

AF:

0.0957

Gnomad4 ASJ exome

AF:

0.137

Gnomad4 EAS exome

AF:

0.240

Gnomad4 SAS exome

AF:

0.208

Gnomad4 FIN exome

AF:

0.121

Gnomad4 NFE exome

AF:

0.154

Gnomad4 OTH exome

AF:

0.191

GnomAD4 genome

AF:

0.259

AC:

39433

AN:

152050

Hom.:

7504

Cov.:

AF XY:

0.255

AC XY:

18932

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.541

Gnomad4 AMR

AF:

0.142

Gnomad4 ASJ

AF:

0.129

Gnomad4 EAS

AF:

0.255

Gnomad4 SAS

AF:

0.215

Gnomad4 FIN

AF:

0.114

Gnomad4 NFE

AF:

0.150

Gnomad4 OTH

AF:

0.229

Alfa

AF:

0.173

Hom.:

4988

Bravo

AF:

0.271

TwinsUK

AF:

0.156

AC:

579

ALSPAC

AF:

0.163

AC:

628

ESP6500AA

AF:

0.535

AC:

2356

ESP6500EA

AF:

0.150

AC:

1293

ExAC

AF:

0.193

AC:

23472

Asia WGS

AF:

0.260

AC:

902

AN:

3478

EpiCase

AF:

0.144

EpiControl

AF:

0.150

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2023	- -

Ehlers-Danlos syndrome, kyphoscoliotic type 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 14, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.0095

.;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.64

T;T;T

MetaRNN

Benign

0.00010

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-2.4

.;.;N

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.42

PROVEAN

Benign

1.4

N;N;N

REVEL

Benign

0.15

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.65

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.091

MPC

0.20

ClinPred

0.0018

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.017

gMVP

0.45

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