3-146070546-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182943.3(PLOD2):c.*171T>G variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0325 in 542,934 control chromosomes in the GnomAD database, including 410 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (102 hom., cov: 32)
  • Exomes 𝑓: 0.034 (308 hom.)
• Consequence: PLOD2 NM_182943.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.59

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 3-146070546-A-C is Benign according to our data. Variant chr3-146070546-A-C is described in ClinVar as [Benign]. Clinvar id is 343641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0274 (4159/151920) while in subpopulation NFE AF= 0.0368 (2495/67832). AF 95% confidence interval is 0.0356. There are 102 homozygotes in gnomad4. There are 2067 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 95 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLOD2	NM_182943.3	c.*171T>G		3_prime_UTR_variant	20/20	ENST00000282903.10
PLOD2	NM_000935.3	c.*171T>G		3_prime_UTR_variant	19/19
PLOD2	XM_017006625.3	c.*171T>G		3_prime_UTR_variant	21/21
PLOD2	XM_047448319.1	c.*171T>G		3_prime_UTR_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLOD2	ENST00000282903.10	c.*171T>G		3_prime_UTR_variant	20/20	1	NM_182943.3	P3
	ENST00000480247.1	n.337+2368A>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4140 AN: 151802 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.00686

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0359

Gnomad FIN AF: 0.0650

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0368

Gnomad OTH AF: 0.0231

GnomAD4 exome AF: 0.0345 AC: 13485 AN: 391014 Hom.: 308 Cov.: 4 AF XY: 0.0347 AC XY: 7113 AN XY: 204844

Gnomad4 AFR exome AF: 0.00601

Gnomad4 AMR exome AF: 0.0184

Gnomad4 ASJ exome AF: 0.0200

Gnomad4 EAS exome AF: 0.000244

Gnomad4 SAS exome AF: 0.0408

Gnomad4 FIN exome AF: 0.0603

Gnomad4 NFE exome AF: 0.0369

Gnomad4 OTH exome AF: 0.0345

GnomAD4 genome AF: 0.0274 AC: 4159 AN: 151920 Hom.: 102 Cov.: 32 AF XY: 0.0278 AC XY: 2067 AN XY: 74262

Gnomad4 AFR AF: 0.00684

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.0359

Gnomad4 FIN AF: 0.0650

Gnomad4 NFE AF: 0.0368

Gnomad4 OTH AF: 0.0324

Alfa AF: 0.0306 Hom.: 9

Bravo AF: 0.0225

Asia WGS AF: 0.0320 AC: 113 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	16
Dann	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs13079521; hg19: chr3-145788333;