chr1-11950412-G-T

Variant names:

Variant summary

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

The NM_000302.4(PLOD1):c.358G>T(p.Ala120Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0898 in 1,613,908 control chromosomes in the GnomAD database, including 8,364 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. A120A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.14 ( 2124 hom., cov: 32)

Exomes 𝑓: 0.085 ( 6240 hom. )

Consequence

PLOD1
NM_000302.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.32

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=0.0013234615).

BP6

Variant 1-11950412-G-T is Benign according to our data. Variant chr1-11950412-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 255804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11950412-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLOD1	NM_000302.4 link	c.358G>T	p.Ala120Ser	missense_variant	Exon 4 of 19	ENST00000196061.5	NP_000293.2	Q02809-1
PLOD1	NM_001316320.2 link	c.499G>T	p.Ala167Ser	missense_variant	Exon 5 of 20		NP_001303249.1	Q02809-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5 link	c.358G>T	p.Ala120Ser	missense_variant	Exon 4 of 19	1	NM_000302.4	ENSP00000196061.4		Q02809-1

Frequencies

GnomAD3 genomes

AF:

0.136

AC:

20682

AN:

152084

Hom.:

2119

Cov.:

show subpopulations

Gnomad AFR

AF:

0.287

Gnomad AMI

AF:

0.0735

Gnomad AMR

AF:

0.0826

Gnomad ASJ

AF:

0.0884

Gnomad EAS

AF:

0.120

Gnomad SAS

AF:

0.0635

Gnomad FIN

AF:

0.0371

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0819

Gnomad OTH

AF:

0.123

GnomAD3 exomes

AF:

0.0867

AC:

21778

AN:

251224

Hom.:

1419

AF XY:

0.0824

AC XY:

11182

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.293

Gnomad AMR exome

AF:

0.0466

Gnomad ASJ exome

AF:

0.0944

Gnomad EAS exome

AF:

0.123

Gnomad SAS exome

AF:

0.0591

Gnomad FIN exome

AF:

0.0400

Gnomad NFE exome

AF:

0.0800

Gnomad OTH exome

AF:

0.0718

GnomAD4 exome

AF:

0.0850

AC:

124277

AN:

1461706

Hom.:

6240

Cov.:

AF XY:

0.0831

AC XY:

60428

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.287

Gnomad4 AMR exome

AF:

0.0500

Gnomad4 ASJ exome

AF:

0.0899

Gnomad4 EAS exome

AF:

0.0941

Gnomad4 SAS exome

AF:

0.0572

Gnomad4 FIN exome

AF:

0.0403

Gnomad4 NFE exome

AF:

0.0838

Gnomad4 OTH exome

AF:

0.0964

GnomAD4 genome

AF:

0.136

AC:

20715

AN:

152202

Hom.:

2124

Cov.:

AF XY:

0.133

AC XY:

9906

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.287

Gnomad4 AMR

AF:

0.0824

Gnomad4 ASJ

AF:

0.0884

Gnomad4 EAS

AF:

0.120

Gnomad4 SAS

AF:

0.0638

Gnomad4 FIN

AF:

0.0371

Gnomad4 NFE

AF:

0.0819

Gnomad4 OTH

AF:

0.121

Alfa

AF:

0.0917

Hom.:

1770

Bravo

AF:

0.145

TwinsUK

AF:

0.0850

AC:

315

ALSPAC

AF:

0.0867

AC:

334

ESP6500AA

AF:

0.286

AC:

1261

ESP6500EA

AF:

0.0836

AC:

719

ExAC

AF:

0.0918

AC:

11149

Asia WGS

AF:

0.0920

AC:

320

AN:

3478

EpiCase

AF:

0.0808

EpiControl

AF:

0.0856

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 05, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 09, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, kyphoscoliotic type 1

Benign:3

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Jan 29, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

.;T;T

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.82

T;T;T

MetaRNN

Benign

0.0013

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.77

.;.;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.69

N;N;N

REVEL

Benign

0.069

Sift

Benign

0.52

T;T;T

Sift4G

Benign

0.46

T;T;T

Polyphen

0.12

.;.;B

Vest4

0.083

MPC

0.20

ClinPred

0.024

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.040

gMVP

0.57

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