NM_000302.4:c.295G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000302.4(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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. 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
NM_000302.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.26

Publications

35 publications found

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 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome, kyphoscoliotic type 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, PanelApp Australia, G2P

PLOD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 196247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
PLOD1	NM_000302.4 link	c.295G>A	p.Ala99Thr	missense_variant	Exon 3 of 19	ENST00000196061.5	NP_000293.2
PLOD1	NM_001316320.2 link	c.436G>A	p.Ala146Thr	missense_variant	Exon 4 of 20		NP_001303249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5 link	c.295G>A	p.Ala99Thr	missense_variant	Exon 3 of 19	1	NM_000302.4	ENSP00000196061.4

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

GnomAD2 exomes

AF:

0.181

AC:

45490

AN:

251356

AF XY:

0.176

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 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

African (AFR)

AF:

0.546

AC:

18272

AN:

33460

American (AMR)

AF:

0.0957

AC:

4280

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

3570

AN:

26136

East Asian (EAS)

AF:

0.240

AC:

9536

AN:

39690

South Asian (SAS)

AF:

0.208

AC:

17900

AN:

86248

European-Finnish (FIN)

AF:

0.121

AC:

6450

AN:

53394

Middle Eastern (MID)

AF:

0.136

AC:

785

AN:

5764

European-Non Finnish (NFE)

AF:

0.154

AC:

170999

AN:

1111556

Other (OTH)

AF:

0.191

AC:

11535

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

10506

21011

31517

42022

52528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6366

12732

19098

25464

31830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.259

AC:

39433

AN:

152050

Hom.:

7504

Cov.:

AF XY:

0.255

AC XY:

18932

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.541

AC:

22409

AN:

41438

American (AMR)

AF:

0.142

AC:

2163

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.129

AC:

449

AN:

3472

East Asian (EAS)

AF:

0.255

AC:

1316

AN:

5168

South Asian (SAS)

AF:

0.215

AC:

1037

AN:

4820

European-Finnish (FIN)

AF:

0.114

AC:

1206

AN:

10594

Middle Eastern (MID)

AF:

0.146

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.150

AC:

10189

AN:

67974

Other (OTH)

AF:

0.229

AC:

484

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1238

2476

3713

4951

6189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

380

760

1140

1520

1900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.191

Hom.:

9169

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:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 04, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 22, 2015

Eurofins Ntd Llc (ga)

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

- -

Ehlers-Danlos syndrome, kyphoscoliotic type 1

Benign:3

Mar 06, 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. -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Ehlers-Danlos syndrome

Benign:1

Jul 14, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.051

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

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

PhyloP100

1.3

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

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over