1-11965591-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_000302.4(PLOD1):c.1582G>A(p.Glu528Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000173 in 1,598,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

PLOD1
NM_000302.4 missense, splice_region

Scores

Splicing: ADA: 0.0001462

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 4.63

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.016842455).

BP6

Variant 1-11965591-G-A is Benign according to our data. Variant chr1-11965591-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 459811.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000775 (118/152304) while in subpopulation AFR AF= 0.00262 (109/41558). AF 95% confidence interval is 0.00222. There are 0 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLOD1	NM_000302.4 link	c.1582G>A	p.Glu528Lys	missense_variant, splice_region_variant	Exon 14 of 19	ENST00000196061.5	NP_000293.2	Q02809-1
PLOD1	NM_001316320.2 link	c.1723G>A	p.Glu575Lys	missense_variant, splice_region_variant	Exon 15 of 20		NP_001303249.1	Q02809-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PLOD1	ENST00000196061.5 link	c.1582G>A	p.Glu528Lys	missense_variant, splice_region_variant	Exon 14 of 19	1	NM_000302.4	ENSP00000196061.4	Q02809-1
PLOD1	ENST00000470133.1 link	n.196G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	3
PLOD1	ENST00000491536.5 link	n.210G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.000775

AC:

118

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000295

AC:

AN:

250438

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

135528

show subpopulations

Gnomad AFR exome

AF:

0.00333

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.0000974

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000109

AC:

158

AN:

1445848

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

720288

show subpopulations

Gnomad4 AFR exome

AF:

0.00304

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.0000200

Gnomad4 OTH exome

AF:

0.000284

GnomAD4 genome

AF:

0.000775

AC:

118

AN:

152304

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00262

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000185

Hom.:

Bravo

AF:

0.00108

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000412

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 18, 2022	BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2020	- -

Ehlers-Danlos syndrome, kyphoscoliotic type 1

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2025	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 29, 2021	The PLOD1 c.1582G>A; p.Glu528Lys variant (rs112250644), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 459811). This variant is found in the African/African-American population with an allele frequency of 0.27% (68/24928 alleles) in the Genome Aggregation Database. The glutamate at codon 528 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.537). Due to limited information, the clinical significance of the p.Glu528Lys variant is uncertain at this time. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 03, 2024

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 10, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

Eigen

Benign

-0.089

Eigen_PC

Benign

-0.031

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.017

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

1.5

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.50

REVEL

Uncertain

0.54

Sift

Benign

0.29

Sift4G

Benign

0.29

Polyphen

0.63

Vest4

0.69

MVP

0.89

MPC

0.23

ClinPred

0.012

GERP RS

4.6

Varity_R

0.10

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00015

dbscSNV1_RF

Benign

0.0020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over