chr17-45450622-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_014798.3(PLEKHM1):c.2639G>A(p.Arg880His) variant causes a missense change. The variant allele was found at a frequency of 0.0000363 in 1,461,380 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 29)
Exomes 𝑓: 0.000036 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PLEKHM1
NM_014798.3 missense
NM_014798.3 missense
Scores
7
11
Clinical Significance
Conservation
PhyloP100: 4.69
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 Uncertain_significance. Variant got 1 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, PLEKHM1
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEKHM1 | NM_014798.3 | c.2639G>A | p.Arg880His | missense_variant | 8/12 | ENST00000430334.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEKHM1 | ENST00000430334.8 | c.2639G>A | p.Arg880His | missense_variant | 8/12 | 1 | NM_014798.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151992Hom.: 0 Cov.: 29
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.0000717 AC: 18AN: 250904Hom.: 0 AF XY: 0.0000958 AC XY: 13AN XY: 135636
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GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461380Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33AN XY: 726974
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.0000132 AC: 2AN: 151992Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1AN XY: 74228
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Data not reliable, filtered out with message: AS_VQSR
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 13, 2023 | The c.2639G>A (p.R880H) alteration is located in exon 8 (coding exon 7) of the PLEKHM1 gene. This alteration results from a G to A substitution at nucleotide position 2639, causing the arginine (R) at amino acid position 880 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of MoRF binding (P = 0.0071);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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