rs34878020

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.250G>A(p.Ala84Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,614,080 control chromosomes in the GnomAD database, including 293 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 101 hom., cov: 32)

Exomes 𝑓: 0.012 ( 192 hom. )

Consequence

PLOD1
NM_000302.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.06

Publications

12 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=0.0033874512).

BP6

Variant 1-11949854-G-A is Benign according to our data. Variant chr1-11949854-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0621 is higher than 0.05.

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.250G>A	p.Ala84Thr	missense	Exon 3 of 19	NP_000293.2
	PLOD1	NM_001316320.2		c.391G>A	p.Ala131Thr	missense	Exon 4 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.250G>A	p.Ala84Thr	missense	Exon 3 of 19	ENSP00000196061.4	Q02809-1
PLOD1	ENST00000854019.1		c.394G>A	p.Ala132Thr	missense	Exon 4 of 20	ENSP00000524078.1
PLOD1	ENST00000854031.1		c.250G>A	p.Ala84Thr	missense	Exon 3 of 20	ENSP00000524090.1

Frequencies

GnomAD3 genomes

AF:

0.0253

AC:

3843

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0638

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0157

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0174

Gnomad FIN

AF:

0.00565

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0109

Gnomad OTH

AF:

0.0220

GnomAD2 exomes

AF:

0.0137

AC:

3437

AN:

251456

AF XY:

0.0129

show subpopulations

Gnomad AFR exome

AF:

0.0660

Gnomad AMR exome

AF:

0.0102

Gnomad ASJ exome

AF:

0.00804

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00531

Gnomad NFE exome

AF:

0.0103

Gnomad OTH exome

AF:

0.0134

GnomAD4 exome

AF:

0.0124

AC:

18081

AN:

1461778

Hom.:

192

Cov.:

AF XY:

0.0123

AC XY:

8942

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.0650

AC:

2175

AN:

33468

American (AMR)

AF:

0.0104

AC:

467

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00788

AC:

206

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0171

AC:

1478

AN:

86256

European-Finnish (FIN)

AF:

0.00610

AC:

326

AN:

53404

Middle Eastern (MID)

AF:

0.0224

AC:

129

AN:

5768

European-Non Finnish (NFE)

AF:

0.0111

AC:

12311

AN:

1111930

Other (OTH)

AF:

0.0163

AC:

984

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

995

1990

2986

3981

4976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

522

1044

1566

2088

2610

<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:

0.0254

AC:

3866

AN:

152302

Hom.:

101

Cov.:

AF XY:

0.0247

AC XY:

1837

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0642

AC:

2667

AN:

41566

American (AMR)

AF:

0.0156

AC:

239

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.0178

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00565

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0109

AC:

744

AN:

68024

Other (OTH)

AF:

0.0218

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

187

374

560

747

934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0146

Hom.:

Bravo

AF:

0.0276

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.0617

AC:

272

ESP6500EA

AF:

0.0114

AC:

ExAC

AF:

0.0149

AC:

1803

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0122

EpiControl

AF:

0.0118

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Ehlers-Danlos syndrome, kyphoscoliotic type 1 (3)

not provided (2)

Ehlers-Danlos syndrome (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.059

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.86

MetaRNN

Benign

0.0034

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PhyloP100

8.1

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.1

REVEL

Benign

0.082

Sift

Benign

0.086

Sift4G

Benign

0.087

Polyphen

0.63

Vest4

0.20

MPC

0.28

ClinPred

0.052

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.59

Mutation Taster

=93/7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over