rs559224144
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5
The NM_014798.3(PLEKHM1):c.2140C>T(p.Arg714Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,842 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 Pathogenic (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
PLEKHM1
NM_014798.3 missense
NM_014798.3 missense
Scores
2
10
6
Clinical Significance
Conservation
PhyloP100: 2.51
Genes affected
PLEKHM1 (HGNC:29017): (pleckstrin homology and RUN domain containing M1) The protein encoded by this gene is essential for bone resorption, and may play a critical role in vesicular transport in the osteoclast. Mutations in this gene are associated with autosomal recessive osteopetrosis type 6 (OPTB6). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, PLEKHM1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.937
PP5
?
Variant 17-45453712-G-A is Pathogenic according to our data. Variant chr17-45453712-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 560304.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEKHM1 | NM_014798.3 | c.2140C>T | p.Arg714Cys | missense_variant | 7/12 | ENST00000430334.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEKHM1 | ENST00000430334.8 | c.2140C>T | p.Arg714Cys | missense_variant | 7/12 | 1 | NM_014798.3 | P1 | |
ENST00000433601.1 | n.245+624G>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250100Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135372
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461652Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727132
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74394
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Osteopetrosis, autosomal dominant 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 04, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of catalytic residue at R714 (P = 0.0257);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at