1-11964293-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000302.4(PLOD1):c.1321C>T(p.Arg441Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000356 in 533,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R441Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 26)

Exomes 𝑓: 0.00042 ( 0 hom. )

Consequence

PLOD1
NM_000302.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 0.747

Publications

8 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18729547).

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.1321C>T	p.Arg441Trp	missense	Exon 12 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.1462C>T	p.Arg488Trp	missense	Exon 13 of 20	NP_001303249.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLOD1	ENST00000196061.5	TSL:1 MANE Select	c.1321C>T	p.Arg441Trp	missense	Exon 12 of 19	ENSP00000196061.4
PLOD1	ENST00000854019.1		c.1465C>T	p.Arg489Trp	missense	Exon 13 of 20	ENSP00000524078.1
PLOD1	ENST00000854031.1		c.1408C>T	p.Arg470Trp	missense	Exon 13 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes

AF:

0.000144

AC:

AN:

117648

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000322

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000326

Gnomad ASJ

AF:

0.00159

Gnomad EAS

AF:

0.000285

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000100

Gnomad OTH

AF:

0.000620

GnomAD2 exomes

AF:

0.000177

AC:

AN:

248516

AF XY:

0.000216

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000878

Gnomad ASJ exome

AF:

0.00260

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0000489

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000416

AC:

173

AN:

416282

Hom.:

Cov.:

AF XY:

0.000407

AC XY:

AN XY:

225782

show subpopulations

African (AFR)

AF:

0.000176

AC:

AN:

11350

American (AMR)

AF:

0.000167

AC:

AN:

35972

Ashkenazi Jewish (ASJ)

AF:

0.00619

AC:

AN:

12116

East Asian (EAS)

AF:

0.000309

AC:

AN:

12948

South Asian (SAS)

AF:

0.00

AC:

AN:

66966

European-Finnish (FIN)

AF:

0.0000320

AC:

AN:

31202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2842

European-Non Finnish (NFE)

AF:

0.000306

AC:

AN:

225374

Other (OTH)

AF:

0.000914

AC:

AN:

17512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

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:

0.000144

AC:

AN:

117688

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

54732

show subpopulations

African (AFR)

AF:

0.0000322

AC:

AN:

31074

American (AMR)

AF:

0.000326

AC:

AN:

9210

Ashkenazi Jewish (ASJ)

AF:

0.00159

AC:

AN:

3144

East Asian (EAS)

AF:

0.000286

AC:

AN:

3500

South Asian (SAS)

AF:

0.00

AC:

AN:

3188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.000100

AC:

AN:

59794

Other (OTH)

AF:

0.000616

AC:

AN:

1624

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.000247

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000140

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ehlers-Danlos syndrome, kyphoscoliotic type 1 (3)

not provided (2)

Familial thoracic aortic aneurysm and aortic dissection (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.062

MetaRNN

Benign

0.19

MetaSVM

Uncertain

0.28

MutationAssessor

Uncertain

2.4

PhyloP100

0.75

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.63

MVP

0.95

MPC

0.45

ClinPred

0.32

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.80

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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