rs879691

Positions:

• chr1-11974757-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000302.4(PLOD1):​c.2133C>G​(p.Leu711=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0072 in 1,614,006 control chromosomes in the GnomAD database, including 201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (81 hom., cov: 31)
  • Exomes 𝑓: 0.0058 (120 hom.)
• Consequence: PLOD1 NM_000302.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.711

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 1-11974757-C-G is Benign according to our data. Variant chr1-11974757-C-G is described in ClinVar as [Benign]. Clinvar id is 263889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11974757-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.711 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLOD1	NM_000302.4	c.2133C>G	p.Leu711=	synonymous_variant	19/19	ENST00000196061.5	NP_000293.2
PLOD1	NM_001316320.2	c.2274C>G	p.Leu758=	synonymous_variant	20/20		NP_001303249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5	c.2133C>G	p.Leu711=	synonymous_variant	19/19	1	NM_000302.4	ENSP00000196061	P1
PLOD1	ENST00000481933.1	n.1560C>G		non_coding_transcript_exon_variant	2/2	2
PLOD1	ENST00000491536.5	n.384-526C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3080 AN: 152152 Hom.: 81 Cov.: 31

Gnomad AFR AF: 0.0608

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.000564

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00420

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00927 AC: 2329 AN: 251334 Hom.: 48 AF XY: 0.00857 AC XY: 1164 AN XY: 135896

Gnomad AFR exome AF: 0.0646

Gnomad AMR exome AF: 0.00656

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0188

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00367

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00584 AC: 8536 AN: 1461736 Hom.: 120 Cov.: 31 AF XY: 0.00598 AC XY: 4350 AN XY: 727186

Gnomad4 AFR exome AF: 0.0647

Gnomad4 AMR exome AF: 0.00684

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0172

Gnomad4 FIN exome AF: 0.000637

Gnomad4 NFE exome AF: 0.00351

Gnomad4 OTH exome AF: 0.00863

GnomAD4 genome AF: 0.0203 AC: 3085 AN: 152270 Hom.: 81 Cov.: 31 AF XY: 0.0192 AC XY: 1428 AN XY: 74468

Gnomad4 AFR AF: 0.0608

Gnomad4 AMR AF: 0.00948

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0185

Gnomad4 FIN AF: 0.000564

Gnomad4 NFE AF: 0.00421

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.00814 Hom.: 5

Bravo AF: 0.0229

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00462

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 09, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	8.3
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs879691; hg19: chr1-12034814;