rs142710681

Positions:

• chr1-11948036-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_000302.4(PLOD1):​c.137G>A​(p.Arg46His) variant causes a missense change. The variant allele was found at a frequency of 0.000187 in 1,613,714 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R46C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: PLOD1 NM_000302.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 6.75

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030934691).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000906 (138/152238) while in subpopulation AFR AF= 0.00291 (121/41542). AF 95% confidence interval is 0.00249. There are 0 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLOD1	NM_000302.4	c.137G>A	p.Arg46His	missense_variant	2/19	ENST00000196061.5	NP_000293.2
PLOD1	NM_001316320.2	c.278G>A	p.Arg93His	missense_variant	3/20		NP_001303249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5	c.137G>A	p.Arg46His	missense_variant	2/19	1	NM_000302.4	ENSP00000196061.4

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251494 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135922

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000439

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000112 AC: 163 AN: 1461476 Hom.: 1 Cov.: 30 AF XY: 0.0000963 AC XY: 70 AN XY: 727066

Gnomad4 AFR exome AF: 0.00293

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000906 AC: 138 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74434

Gnomad4 AFR AF: 0.00291

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.000163 Hom.: 0

Bravo AF: 0.00112

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2022	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 03, 2017	The p.Arg46His variant (rs142710681) has not been reported in the medical literature, is not listed in gene-specific variant databases, nor has it been previously identified in our laboratory. It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in Africans of 0.25% (identified in 60 out of 24,034 chromosomes). The arginine at codon 46 is highly conserved considering 12 species up to Fruitfly (Alamut software v2.8.1), and computational analyses suggest this variant has a significant effect on PLOD1 protein structure/function (SIFT: damaging, PolyPhen2: possibly damaging, and Mutation Taster: disease causing). However, based on the available information, the clinical significance of the p.Arg46His variant cannot be determined with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 22, 2023	BS1 -

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 16, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2020

The p.R46H variant (also known as c.137G>A), located in coding exon 2 of the PLOD1 gene, results from a G to A substitution at nucleotide position 137. The arginine at codon 46 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

PLOD1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	.;T;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.031	T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.5	.;.;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.99	.;.;D
Vest4		0.72
MVP		0.89
MPC		0.26
ClinPred		0.089	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.30
gMVP		0.76

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

LitVar

Other links and lift over

dbSNP: rs142710681; hg19: chr1-12008093;