chr17-45439514-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BP4_Strong
The NM_014798.3(PLEKHM1):c.3022G>A(p.Asp1008Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00013 in 1,614,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
PLEKHM1
NM_014798.3 missense
NM_014798.3 missense
Scores
5
13
Clinical Significance
Conservation
PhyloP100: 4.90
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_benign. Variant got -3 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, PLEKHM1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.01430729).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEKHM1 | NM_014798.3 | c.3022G>A | p.Asp1008Asn | missense_variant | 11/12 | ENST00000430334.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEKHM1 | ENST00000430334.8 | c.3022G>A | p.Asp1008Asn | missense_variant | 11/12 | 1 | NM_014798.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000243 AC: 37AN: 152208Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000123 AC: 31AN: 251362Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135904
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GnomAD4 exome AF: 0.000118 AC: 173AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.000128 AC XY: 93AN XY: 727236
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GnomAD4 genome ? AF: 0.000243 AC: 37AN: 152326Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18AN XY: 74484
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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 | Jan 10, 2022 | The c.3022G>A (p.D1008N) alteration is located in exon 11 (coding exon 10) of the PLEKHM1 gene. This alteration results from a G to A substitution at nucleotide position 3022, causing the aspartic acid (D) at amino acid position 1008 to be replaced by an asparagine (N). 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
Benign
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
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