rs73010484

Variant names:

• chr3-146079104-T-C
• rs73010484
• NM_182943.3:c.1500+12A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-146079104-T-C
• chr3-146079104-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182943.3(PLOD2):​c.1500+12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,609,696 control chromosomes in the GnomAD database, including 64,442 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4884 hom., cov: 32)
  • Exomes 𝑓: 0.28 (59558 hom.)
• Consequence: PLOD2 NM_182943.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.39
• Publications: 7 publications found

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]

PLOD2 Gene-Disease associations (from GenCC):

• Bruck syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Bruck syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000243415 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 3-146079104-T-C is Benign according to our data. Variant chr3-146079104-T-C is described in ClinVar as Benign. ClinVar VariationId is 263073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182943.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLOD2	NM_182943.3	MANE Select	c.1500+12A>G		intron	N/A	NP_891988.1	O00469-2
	PLOD2	NM_000935.3		c.1500+12A>G		intron	N/A	NP_000926.2	O00469-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLOD2	ENST00000282903.10	TSL:1 MANE Select	c.1500+12A>G		intron	N/A	ENSP00000282903.5	O00469-2
	PLOD2	ENST00000360060.7	TSL:1	c.1500+12A>G		intron	N/A	ENSP00000353170.3	O00469-1
	PLOD2	ENST00000478436.1	TSL:1	n.1835+12A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37805 AN: 151620 Hom.: 4877 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.252

GnomAD2 exomes AF: 0.269 AC: 67633 AN: 251140 AF XY: 0.268

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.287

Gnomad ASJ exome AF: 0.266

Gnomad EAS exome AF: 0.254

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.263

GnomAD4 exome AF: 0.283 AC: 411958 AN: 1457960 Hom.: 59558 Cov.: 31 AF XY: 0.280 AC XY: 203294 AN XY: 725476

African (AFR) AF: 0.179 AC: 5978 AN: 33392

American (AMR) AF: 0.288 AC: 12865 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 6869 AN: 26086

East Asian (EAS) AF: 0.297 AC: 11769 AN: 39594

South Asian (SAS) AF: 0.234 AC: 20180 AN: 86164

European-Finnish (FIN) AF: 0.228 AC: 12153 AN: 53352

Middle Eastern (MID) AF: 0.259 AC: 1490 AN: 5752

European-Non Finnish (NFE) AF: 0.293 AC: 324645 AN: 1108668

Other (OTH) AF: 0.266 AC: 16009 AN: 60242

GnomAD4 genome AF: 0.249 AC: 37818 AN: 151736 Hom.: 4884 Cov.: 32 AF XY: 0.246 AC XY: 18221 AN XY: 74128

African (AFR) AF: 0.183 AC: 7582 AN: 41474

American (AMR) AF: 0.266 AC: 4036 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 885 AN: 3470

East Asian (EAS) AF: 0.268 AC: 1379 AN: 5146

South Asian (SAS) AF: 0.255 AC: 1229 AN: 4820

European-Finnish (FIN) AF: 0.234 AC: 2474 AN: 10570

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.288 AC: 19492 AN: 67744

Other (OTH) AF: 0.252 AC: 530 AN: 2106

Alfa AF: 0.195 Hom.: 636

Bravo AF: 0.251

Asia WGS AF: 0.270 AC: 937 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Bruck syndrome 2 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.094
DANN	Benign	0.69
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs73010484; hg19: chr3-145796891; COSMIC: COSV51466717; COSMIC: COSV51466717;