rs4681297

Positions:

• chr3-146121108-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182943.3(PLOD2):​c.338+4G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 1,585,818 control chromosomes in the GnomAD database, including 467,888 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (46019 hom., cov: 31)
  • Exomes 𝑓: 0.77 (421869 hom.)
• Consequence: PLOD2 NM_182943.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00004899
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.509

Genes affected

PLOD2 (HGNC:9082): (procollagen-lysine,2-oxoglutarate 5-dioxygenase 2) The protein encoded by this gene is a membrane-bound homodimeric enzyme that is localized to the cisternae of the rough 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 VIB have deficiencies in lysyl hydroxylase activity. Mutations in the coding region of this gene are associated with Bruck syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 3-146121108-C-T is Benign according to our data. Variant chr3-146121108-C-T is described in ClinVar as [Benign]. Clinvar id is 263074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-146121108-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLOD2	NM_182943.3	c.338+4G>A		splice_donor_region_variant, intron_variant		ENST00000282903.10	NP_891988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLOD2	ENST00000282903.10	c.338+4G>A		splice_donor_region_variant, intron_variant		1	NM_182943.3	ENSP00000282903	P3

Frequencies

GnomAD3 genomes AF: 0.777 AC: 118090 AN: 151902 Hom.: 45978 Cov.: 31

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.730

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.833

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.707

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.769

Gnomad OTH AF: 0.782

GnomAD3 exomes AF: 0.765 AC: 191652 AN: 250686 Hom.: 73495 AF XY: 0.763 AC XY: 103442 AN XY: 135516

Gnomad AFR exome AF: 0.813

Gnomad AMR exome AF: 0.725

Gnomad ASJ exome AF: 0.842

Gnomad EAS exome AF: 0.846

Gnomad SAS exome AF: 0.731

Gnomad FIN exome AF: 0.710

Gnomad NFE exome AF: 0.769

Gnomad OTH exome AF: 0.772

GnomAD4 exome AF: 0.766 AC: 1098486 AN: 1433798 Hom.: 421869 Cov.: 28 AF XY: 0.765 AC XY: 547281 AN XY: 715498

Gnomad4 AFR exome AF: 0.819

Gnomad4 AMR exome AF: 0.728

Gnomad4 ASJ exome AF: 0.847

Gnomad4 EAS exome AF: 0.805

Gnomad4 SAS exome AF: 0.731

Gnomad4 FIN exome AF: 0.704

Gnomad4 NFE exome AF: 0.768

Gnomad4 OTH exome AF: 0.778

GnomAD4 genome AF: 0.777 AC: 118189 AN: 152020 Hom.: 46019 Cov.: 31 AF XY: 0.773 AC XY: 57413 AN XY: 74270

Gnomad4 AFR AF: 0.815

Gnomad4 AMR AF: 0.743

Gnomad4 ASJ AF: 0.840

Gnomad4 EAS AF: 0.833

Gnomad4 SAS AF: 0.728

Gnomad4 FIN AF: 0.707

Gnomad4 NFE AF: 0.769

Gnomad4 OTH AF: 0.785

Alfa AF: 0.779 Hom.: 96027

Bravo AF: 0.783

Asia WGS AF: 0.801 AC: 2786 AN: 3478

EpiCase AF: 0.776

EpiControl AF: 0.774

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2017	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	Eurofins Ntd Llc (ga)	Jun 22, 2015	- -

Bruck syndrome 2 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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	-0.79
CADD	Benign	17
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
dbscSNV1_RF	Benign	0.018
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: rs4681297; hg19: chr3-145838895;