rs41281013

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001084.5(PLOD3):c.1144G>C(p.Asp382His) variant causes a missense change. The variant allele was found at a frequency of 0.00725 in 1,605,936 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts 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. D382D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0057 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0074 ( 60 hom. )

Consequence

PLOD3
NM_001084.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.94

Publications

8 publications found

Variant links:

Genes affected

PLOD3 (HGNC:9083): (procollagen-lysine,2-oxoglutarate 5-dioxygenase 3) The protein encoded by this gene is a membrane-bound homodimeric enzyme that is localized to the cisternae of the rough 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 VIB have deficiencies in lysyl hydroxylase activity. [provided by RefSeq, Jul 2008]

PLOD3 Gene-Disease associations (from GenCC):

bone fragility with contractures, arterial rupture, and deafness
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

PLOD3 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=0.016706944).

BP6

Variant 7-101211934-C-G is Benign according to our data. Variant chr7-101211934-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 440182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00571 (869/152258) while in subpopulation NFE AF = 0.0096 (653/68010). AF 95% confidence interval is 0.00899. There are 7 homozygotes in GnomAd4. There are 390 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLOD3	NM_001084.5 link	c.1144G>C	p.Asp382His	missense_variant	Exon 11 of 19	ENST00000223127.8	NP_001075.1	O60568Q9UG85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLOD3	ENST00000223127.8 link	c.1144G>C	p.Asp382His	missense_variant	Exon 11 of 19	1	NM_001084.5	ENSP00000223127.3		O60568

Frequencies

GnomAD3 genomes

AF:

0.00570

AC:

867

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.0297

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00960

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.00586

AC:

1370

AN:

233818

AF XY:

0.00604

show subpopulations

Gnomad AFR exome

AF:

0.00137

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.0155

Gnomad EAS exome

AF:

0.0000573

Gnomad FIN exome

AF:

0.00192

Gnomad NFE exome

AF:

0.00934

Gnomad OTH exome

AF:

0.00815

GnomAD4 exome

AF:

0.00741

AC:

10767

AN:

1453678

Hom.:

Cov.:

AF XY:

0.00737

AC XY:

5323

AN XY:

722540

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

33352

American (AMR)

AF:

0.00278

AC:

121

AN:

43478

Ashkenazi Jewish (ASJ)

AF:

0.0149

AC:

386

AN:

25936

East Asian (EAS)

AF:

0.00

AC:

AN:

39392

South Asian (SAS)

AF:

0.00158

AC:

134

AN:

84982

European-Finnish (FIN)

AF:

0.00235

AC:

123

AN:

52442

Middle Eastern (MID)

AF:

0.0143

AC:

AN:

5506

European-Non Finnish (NFE)

AF:

0.00849

AC:

9413

AN:

1108578

Other (OTH)

AF:

0.00778

AC:

467

AN:

60012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

519

1038

1557

2076

2595

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

324

648

972

1296

1620

<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:

0.00571

AC:

869

AN:

152258

Hom.:

Cov.:

AF XY:

0.00524

AC XY:

390

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41558

American (AMR)

AF:

0.00307

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00166

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00960

AC:

653

AN:

68010

Other (OTH)

AF:

0.00474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

100

151

201

251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00899

Hom.:

Bravo

AF:

0.00578

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00919

AC:

ExAC

AF:

0.00582

AC:

706

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Sep 18, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PLOD3: BP4, BS2 -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Bone fragility with contractures, arterial rupture, and deafness

Benign:2

Sep 25, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.67

Eigen

Benign

0.17

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.6

PhyloP100

4.9

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.65

Sift

Benign

0.098

Sift4G

Benign

0.11

Polyphen

0.95

Vest4

0.74

MVP

0.93

MPC

0.16

ClinPred

0.060

GERP RS

3.4

PromoterAI

0.0092

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.33

gMVP

0.74

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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