rs879690

Positions:

• chr1-11974748-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000302.4(PLOD1):​c.2124T>C​(p.His708His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,613,982 control chromosomes in the GnomAD database, including 870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (392 hom., cov: 31)
  • Exomes 𝑓: 0.010 (478 hom.)
• Consequence: PLOD1 NM_000302.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.480

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-11974748-T-C is Benign according to our data. Variant chr1-11974748-T-C is described in ClinVar as [Benign]. Clinvar id is 263886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11974748-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.48 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLOD1	NM_000302.4	c.2124T>C	p.His708His	synonymous_variant	19/19	ENST00000196061.5	NP_000293.2
PLOD1	NM_001316320.2	c.2265T>C	p.His755His	synonymous_variant	20/20		NP_001303249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5	c.2124T>C	p.His708His	synonymous_variant	19/19	1	NM_000302.4	ENSP00000196061.4
PLOD1	ENST00000481933.1	n.1551T>C		non_coding_transcript_exon_variant	2/2	2
PLOD1	ENST00000491536.5	n.384-535T>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0434 AC: 6604 AN: 152104 Hom.: 391 Cov.: 31

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0412

Gnomad SAS AF: 0.0302

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00446

Gnomad OTH AF: 0.0320

GnomAD3 exomes AF: 0.0201 AC: 5054 AN: 251340 Hom.: 226 AF XY: 0.0184 AC XY: 2494 AN XY: 135900

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.0430

Gnomad SAS exome AF: 0.0333

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00404

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0100 AC: 14628 AN: 1461760 Hom.: 478 Cov.: 31 AF XY: 0.0102 AC XY: 7381 AN XY: 727186

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.0345

Gnomad4 SAS exome AF: 0.0303

Gnomad4 FIN exome AF: 0.000637

Gnomad4 NFE exome AF: 0.00364

Gnomad4 OTH exome AF: 0.0169

GnomAD4 genome AF: 0.0436 AC: 6631 AN: 152222 Hom.: 392 Cov.: 31 AF XY: 0.0421 AC XY: 3130 AN XY: 74424

Gnomad4 AFR AF: 0.135

Gnomad4 AMR AF: 0.0176

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0413

Gnomad4 SAS AF: 0.0304

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00446

Gnomad4 OTH AF: 0.0345

Alfa AF: 0.0145 Hom.: 125

Bravo AF: 0.0495

Asia WGS AF: 0.0440 AC: 154 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00504

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Benign:3

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.1
DANN	Benign	0.53
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: rs879690; hg19: chr1-12034805;