NM_000302.4:c.1495C>T

Variant names:

Variant summary

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

The NM_000302.4(PLOD1):c.1495C>T(p.Arg499Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000423 in 1,613,106 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00043 ( 2 hom. )

Consequence

PLOD1
NM_000302.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.33

Publications

10 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: Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

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=0.031227767).

BP6

Variant 1-11965504-C-T is Benign according to our data. Variant chr1-11965504-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000394 (60/152242) while in subpopulation EAS AF = 0.00598 (31/5180). AF 95% confidence interval is 0.00433. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000302.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLOD1	NM_000302.4	MANE Select	c.1495C>T	p.Arg499Trp	missense	Exon 14 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.1636C>T	p.Arg546Trp	missense	Exon 15 of 20	NP_001303249.1	Q02809-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLOD1	ENST00000196061.5	TSL:1 MANE Select	c.1495C>T	p.Arg499Trp	missense	Exon 14 of 19	ENSP00000196061.4	Q02809-1
PLOD1	ENST00000854019.1		c.1639C>T	p.Arg547Trp	missense	Exon 15 of 20	ENSP00000524078.1
PLOD1	ENST00000854031.1		c.1582C>T	p.Arg528Trp	missense	Exon 15 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00597

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000828

AC:

208

AN:

251170

AF XY:

0.000802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.00636

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000426

AC:

623

AN:

1460864

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

333

AN XY:

726768

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.000179

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00279

AC:

AN:

26130

East Asian (EAS)

AF:

0.00723

AC:

287

AN:

39696

South Asian (SAS)

AF:

0.00104

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.0000377

AC:

AN:

53078

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000873

AC:

AN:

1111392

Other (OTH)

AF:

0.000630

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000394

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41538

American (AMR)

AF:

0.000196

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00598

AC:

AN:

5180

South Asian (SAS)

AF:

0.00124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000374

Hom.:

Bravo

AF:

0.000404

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000873

AC:

106

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Ehlers-Danlos syndrome, kyphoscoliotic type 1 (2)

Familial thoracic aortic aneurysm and aortic dissection (1)

not specified (1)

PLOD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.031

MetaSVM

Uncertain

0.50

MutationAssessor

Uncertain

2.2

PhyloP100

1.3

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-5.1

REVEL

Uncertain

0.57

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.71

MVP

0.94

MPC

0.30

ClinPred

0.11

GERP RS

4.6

Varity_R

0.47

gMVP

0.87

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over