3-146069870-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_182943.3(PLOD2):c.*847C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0995 in 151,912 control chromosomes in the GnomAD database, including 896 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.10 (896 hom., cov: 32)
  • Exomes 𝑓: 0.088 (0 hom.)
• Consequence: PLOD2 NM_182943.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0180

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-146069870-G-A is Benign according to our data. Variant chr3-146069870-G-A is described in ClinVar as [Benign]. Clinvar id is 343635.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLOD2	NM_182943.3	c.*847C>T		3_prime_UTR_variant	20/20	ENST00000282903.10
PLOD2	NM_000935.3	c.*847C>T		3_prime_UTR_variant	19/19
PLOD2	XM_017006625.3	c.*847C>T		3_prime_UTR_variant	21/21
PLOD2	XM_047448319.1	c.*847C>T		3_prime_UTR_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLOD2	ENST00000282903.10	c.*847C>T		3_prime_UTR_variant	20/20	1	NM_182943.3	P3
	ENST00000480247.1	n.337+1692G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0995 AC: 15066 AN: 151376 Hom.: 892 Cov.: 32

Gnomad AFR AF: 0.0626

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0883

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.0813

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.106

GnomAD4 exome AF: 0.0881 AC: 37 AN: 420 Hom.: 0 Cov.: 0 AF XY: 0.0945 AC XY: 24 AN XY: 254

Gnomad4 FIN exome AF: 0.0894

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0995 AC: 15077 AN: 151492 Hom.: 896 Cov.: 32 AF XY: 0.0999 AC XY: 7392 AN XY: 73984

Gnomad4 AFR AF: 0.0626

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.0883

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.0813

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.105

Alfa AF: 0.106 Hom.: 821

Bravo AF: 0.104

Asia WGS AF: 0.143 AC: 498 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bruck syndrome 2 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	3.3
Dann	Benign	0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs3792347; hg19: chr3-145787657;