Genetic Variant PLOD1:p.His536Gln (chr1-11966274-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000302.4(PLOD1):c.1608C>G(p.His536Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H536H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PLOD1
NM_000302.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.682

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLOD1	NM_000302.4 link	c.1608C>G	p.His536Gln	missense_variant	Exon 15 of 19	ENST00000196061.5	NP_000293.2	Q02809-1
PLOD1	NM_001316320.2 link	c.1749C>G	p.His583Gln	missense_variant	Exon 16 of 20		NP_001303249.1	Q02809-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PLOD1	ENST00000196061.5 link	c.1608C>G	p.His536Gln	missense_variant	Exon 15 of 19	1	NM_000302.4	ENSP00000196061.4	Q02809-1
PLOD1	ENST00000470133.1 link	n.222C>G		non_coding_transcript_exon_variant	Exon 3 of 3	3
PLOD1	ENST00000491536.5 link	n.236C>G		non_coding_transcript_exon_variant	Exon 3 of 5	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455744

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723502

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33340

American (AMR)

AF:

0.00

AC:

AN:

44184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25960

East Asian (EAS)

AF:

0.00

AC:

AN:

39496

South Asian (SAS)

AF:

0.00

AC:

AN:

84886

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52862

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1109044

Other (OTH)

AF:

0.00

AC:

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

7.3

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.70

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.65

M_CAP

Benign

0.061

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.61

MutationAssessor

Pathogenic

3.0

PhyloP100

-0.68

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.61

Sift

Uncertain

0.012

Sift4G

Uncertain

0.016

Polyphen

1.0

Vest4

0.93

MVP

0.76

MPC

0.72

ClinPred

1.0

GERP RS

-8.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.94

Mutation Taster

=34/66

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over