rs763409574

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000302.4(PLOD1):ā€‹c.1172A>Gā€‹(p.Asn391Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,600,930 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N391K) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.00018 ( 2 hom., cov: 32)
Exomes š‘“: 0.00011 ( 0 hom. )

Consequence

PLOD1
NM_000302.4 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 3.54
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0111659765).
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PLOD1NM_000302.4 linkuse as main transcriptc.1172A>G p.Asn391Ser missense_variant 11/19 ENST00000196061.5 NP_000293.2 Q02809-1
PLOD1NM_001316320.2 linkuse as main transcriptc.1313A>G p.Asn438Ser missense_variant 12/20 NP_001303249.1 Q02809-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PLOD1ENST00000196061.5 linkuse as main transcriptc.1172A>G p.Asn391Ser missense_variant 11/191 NM_000302.4 ENSP00000196061.4 Q02809-1

Frequencies

GnomAD3 genomes
AF:
0.000177
AC:
27
AN:
152122
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00403
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000216
AC:
49
AN:
227248
Hom.:
0
AF XY:
0.000221
AC XY:
27
AN XY:
122424
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00370
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000520
Gnomad NFE exome
AF:
0.000107
Gnomad OTH exome
AF:
0.000357
GnomAD4 exome
AF:
0.000107
AC:
155
AN:
1448808
Hom.:
0
Cov.:
31
AF XY:
0.000100
AC XY:
72
AN XY:
719362
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00369
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000120
Gnomad4 FIN exome
AF:
0.0000958
Gnomad4 NFE exome
AF:
0.0000380
Gnomad4 OTH exome
AF:
0.000200
GnomAD4 genome
AF:
0.000177
AC:
27
AN:
152122
Hom.:
2
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74310
show subpopulations
Gnomad4 AFR
AF:
0.0000966
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00403
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000393
Hom.:
1
Bravo
AF:
0.000147
ExAC
AF:
0.000157
AC:
19

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Uncertain:2Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Uncertain significance, no assertion criteria providedclinical testingPG23_Medical Genetics Lab, ASST Papa Giovanni XXIII-- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 30, 2024The p.N391S variant (also known as c.1172A>G), located in coding exon 11 of the PLOD1 gene, results from an A to G substitution at nucleotide position 1172. The asparagine at codon 391 is replaced by serine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 25, 2020In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
PLOD1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJun 17, 2024This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.060
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
13
DANN
Uncertain
0.98
DEOGEN2
Benign
0.064
T
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.35
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.22
T
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.011
T
MetaSVM
Benign
-0.70
T
MutationAssessor
Benign
0.93
L
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.69
N
REVEL
Benign
0.25
Sift
Benign
0.46
T
Sift4G
Benign
0.47
T
Polyphen
0.0060
B
Vest4
0.17
MVP
0.87
MPC
0.16
ClinPred
0.051
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.098
gMVP
0.35

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

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

Other links and lift over

dbSNP: rs763409574; hg19: chr1-12023663; API