1-11958592-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000302.4(PLOD1):​c.920G>A​(p.Arg307Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R307W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

PLOD1
NM_000302.4 missense

Scores

7
6
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PLOD1NM_000302.4 linkuse as main transcriptc.920G>A p.Arg307Gln missense_variant 9/19 ENST00000196061.5
PLOD1NM_001316320.2 linkuse as main transcriptc.1061G>A p.Arg354Gln missense_variant 10/20

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PLOD1ENST00000196061.5 linkuse as main transcriptc.920G>A p.Arg307Gln missense_variant 9/191 NM_000302.4 P1Q02809-1
PLOD1ENST00000465920.1 linkuse as main transcriptn.870G>A non_coding_transcript_exon_variant 4/45
PLOD1ENST00000485046.5 linkuse as main transcriptn.963G>A non_coding_transcript_exon_variant 9/95

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152094
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461846
Hom.:
0
Cov.:
32
AF XY:
0.0000165
AC XY:
12
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000171
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152094
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74278
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, kyphoscoliotic type 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 19, 2021This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 307 of the PLOD1 protein (p.Arg307Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PLOD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 459835). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.080
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.44
T
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D
M_CAP
Benign
0.069
D
MetaRNN
Pathogenic
0.87
D
MetaSVM
Uncertain
0.46
D
MutationAssessor
Uncertain
2.2
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.46
T
PROVEAN
Uncertain
-2.8
D
REVEL
Pathogenic
0.69
Sift
Benign
0.18
T
Sift4G
Benign
0.11
T
Polyphen
1.0
D
Vest4
0.78
MVP
0.97
MPC
0.66
ClinPred
0.98
D
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.29
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.25
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.25
Position offset: 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: rs960778465; hg19: chr1-12018649; COSMIC: COSV99050285; COSMIC: COSV99050285; API