rs2273286

Variant names:

• chr1-11952352-A-G
• rs2273286
• NM_000302.4:c.467-271A>G

Variant summary

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

The NM_000302.4(PLOD1):​c.467-271A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0646 in 152,188 control chromosomes in the GnomAD database, including 387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.065 (387 hom., cov: 32)
• Consequence: PLOD1 NM_000302.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.199
• Publications: 5 publications found

Genes affected

PLOD1 (HGNC:9081): (procollagen-lysine,2-oxoglutarate 5-dioxygenase 1) Lysyl hydroxylase is a membrane-bound homodimeric protein localized to the cisternae of the 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 VI have deficiencies in lysyl hydroxylase activity. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PLOD1 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, kyphoscoliotic type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, PanelApp Australia, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-11952352-A-G is Benign according to our data. Variant chr1-11952352-A-G is described in ClinVar as Benign. ClinVar VariationId is 669464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLOD1	NM_000302.4	c.467-271A>G		intron_variant	Intron 4 of 18	ENST00000196061.5	NP_000293.2
PLOD1	NM_001316320.2	c.608-271A>G		intron_variant	Intron 5 of 19		NP_001303249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLOD1	ENST00000196061.5	c.467-271A>G		intron_variant	Intron 4 of 18	1	NM_000302.4	ENSP00000196061.4

Frequencies

GnomAD3 genomes AF: 0.0646 AC: 9830 AN: 152070 Hom.: 386 Cov.: 32

Gnomad AFR AF: 0.0736

Gnomad AMI AF: 0.0769

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.0723

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0562

Gnomad OTH AF: 0.0594

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0646 AC: 9832 AN: 152188 Hom.: 387 Cov.: 32 AF XY: 0.0654 AC XY: 4869 AN XY: 74418

African (AFR) AF: 0.0735 AC: 3052 AN: 41536

American (AMR) AF: 0.0320 AC: 490 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 91 AN: 3470

East Asian (EAS) AF: 0.147 AC: 761 AN: 5168

South Asian (SAS) AF: 0.134 AC: 648 AN: 4824

European-Finnish (FIN) AF: 0.0723 AC: 765 AN: 10582

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0562 AC: 3823 AN: 68000

Other (OTH) AF: 0.0593 AC: 125 AN: 2108

Alfa AF: 0.0588 Hom.: 171

Bravo AF: 0.0604

Asia WGS AF: 0.141 AC: 490 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.7
DANN	Benign	0.44
PhyloP100		0.20
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: rs2273286; hg19: chr1-12012409;