rs7529452

Variant names:

• chr1-11949898-C-T
• rs7529452
• NM_000302.4:c.294C>T

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.294C>T​(p.Phe98Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,613,408 control chromosomes in the GnomAD database, including 82,689 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6299 hom., cov: 32)
  • Exomes 𝑓: 0.32 (76390 hom.)
• Consequence: PLOD1 NM_000302.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.08

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=-0.41).
• BP6: Variant 1-11949898-C-T is Benign according to our data. Variant chr1-11949898-C-T is described in ClinVar as [Benign]. Clinvar id is 255803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11949898-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLOD1	NM_000302.4	c.294C>T	p.Phe98Phe	synonymous_variant	Exon 3 of 19	ENST00000196061.5	NP_000293.2
PLOD1	NM_001316320.2	c.435C>T	p.Phe145Phe	synonymous_variant	Exon 4 of 20		NP_001303249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5	c.294C>T	p.Phe98Phe	synonymous_variant	Exon 3 of 19	1	NM_000302.4	ENSP00000196061.4

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38595 AN: 151958 Hom.: 6298 Cov.: 32

Gnomad AFR AF: 0.0637

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.274

GnomAD3 exomes AF: 0.329 AC: 82814 AN: 251354 Hom.: 14831 AF XY: 0.336 AC XY: 45707 AN XY: 135858

Gnomad AFR exome AF: 0.0589

Gnomad AMR exome AF: 0.352

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.375

Gnomad SAS exome AF: 0.424

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.316

Gnomad OTH exome AF: 0.331

GnomAD4 exome AF: 0.317 AC: 463265 AN: 1461332 Hom.: 76390 Cov.: 36 AF XY: 0.321 AC XY: 233607 AN XY: 726970

Gnomad4 AFR exome AF: 0.0541

Gnomad4 AMR exome AF: 0.351

Gnomad4 ASJ exome AF: 0.220

Gnomad4 EAS exome AF: 0.343

Gnomad4 SAS exome AF: 0.428

Gnomad4 FIN exome AF: 0.446

Gnomad4 NFE exome AF: 0.311

Gnomad4 OTH exome AF: 0.309

GnomAD4 genome AF: 0.254 AC: 38608 AN: 152076 Hom.: 6299 Cov.: 32 AF XY: 0.262 AC XY: 19467 AN XY: 74308

Gnomad4 AFR AF: 0.0635

Gnomad4 AMR AF: 0.289

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.378

Gnomad4 SAS AF: 0.431

Gnomad4 FIN AF: 0.437

Gnomad4 NFE AF: 0.315

Gnomad4 OTH AF: 0.277

Alfa AF: 0.294 Hom.: 9069

Bravo AF: 0.231

Asia WGS AF: 0.390 AC: 1354 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Apr 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Benign:4

Jul 30, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Jan 23, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Benign	0.82
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: rs7529452; hg19: chr1-12009955; COSMIC: COSV52144592; COSMIC: COSV52144592;