3-146070680-T-C

Position:

• chr3-146070680-T-C

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.*37A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,436,042 control chromosomes in the GnomAD database, including 178,195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20301 hom., cov: 32)
  • Exomes 𝑓: 0.49 (157894 hom.)
• Consequence: PLOD2 NM_182943.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.679

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=-0.88).
• BP6: Variant 3-146070680-T-C is Benign according to our data. Variant chr3-146070680-T-C is described in ClinVar as [Benign]. Clinvar id is 343643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLOD2	NM_182943.3	c.*37A>G		3_prime_UTR_variant	20/20	ENST00000282903.10
PLOD2	NM_000935.3	c.*37A>G		3_prime_UTR_variant	19/19
PLOD2	XM_017006625.3	c.*37A>G		3_prime_UTR_variant	21/21
PLOD2	XM_047448319.1	c.*37A>G		3_prime_UTR_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLOD2	ENST00000282903.10	c.*37A>G		3_prime_UTR_variant	20/20	1	NM_182943.3	P3
	ENST00000480247.1	n.337+2502T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78164 AN: 151388 Hom.: 20272 Cov.: 32

Gnomad AFR AF: 0.553

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.483

Gnomad ASJ AF: 0.593

Gnomad EAS AF: 0.563

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.525

GnomAD3 exomes AF: 0.501 AC: 121396 AN: 242368 Hom.: 30712 AF XY: 0.502 AC XY: 65832 AN XY: 131102

Gnomad AFR exome AF: 0.550

Gnomad AMR exome AF: 0.444

Gnomad ASJ exome AF: 0.585

Gnomad EAS exome AF: 0.592

Gnomad SAS exome AF: 0.501

Gnomad FIN exome AF: 0.484

Gnomad NFE exome AF: 0.491

Gnomad OTH exome AF: 0.519

GnomAD4 exome AF: 0.494 AC: 634655 AN: 1284536 Hom.: 157894 Cov.: 17 AF XY: 0.495 AC XY: 320910 AN XY: 647668

Gnomad4 AFR exome AF: 0.553

Gnomad4 AMR exome AF: 0.446

Gnomad4 ASJ exome AF: 0.589

Gnomad4 EAS exome AF: 0.505

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.484

Gnomad4 NFE exome AF: 0.490

Gnomad4 OTH exome AF: 0.518

GnomAD4 genome AF: 0.516 AC: 78235 AN: 151506 Hom.: 20301 Cov.: 32 AF XY: 0.515 AC XY: 38134 AN XY: 74030

Gnomad4 AFR AF: 0.553

Gnomad4 AMR AF: 0.483

Gnomad4 ASJ AF: 0.593

Gnomad4 EAS AF: 0.563

Gnomad4 SAS AF: 0.476

Gnomad4 FIN AF: 0.481

Gnomad4 NFE AF: 0.501

Gnomad4 OTH AF: 0.529

Alfa AF: 0.517 Hom.: 4239

Bravo AF: 0.518

Asia WGS AF: 0.529 AC: 1843 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bruck syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
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

Jun 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.8
DANN	Benign	0.47

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: rs6710; hg19: chr3-145788467; COSMIC: COSV51463890; COSMIC: COSV51463890;