chr17-45453472-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_014798.3(PLEKHM1):c.2380G>T(p.Asp794Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PLEKHM1
NM_014798.3 missense
NM_014798.3 missense
Scores
1
10
7
Clinical Significance
Conservation
PhyloP100: 3.83
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]
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;
PP2
?
Missense variant where missense usually causes diseases, PLEKHM1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.779
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEKHM1 | NM_014798.3 | c.2380G>T | p.Asp794Tyr | missense_variant | 7/12 | ENST00000430334.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEKHM1 | ENST00000430334.8 | c.2380G>T | p.Asp794Tyr | missense_variant | 7/12 | 1 | NM_014798.3 | P1 | |
ENST00000433601.1 | n.245+384C>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD3 exomes AF: 0.00000488 AC: 1AN: 204976Hom.: 0 AF XY: 0.00000903 AC XY: 1AN XY: 110780
GnomAD3 exomes
AF:
AC:
1
AN:
204976
Hom.:
AF XY:
AC XY:
1
AN XY:
110780
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000275 AC: 4AN: 1454346Hom.: 0 Cov.: 32 AF XY: 0.00000415 AC XY: 3AN XY: 723038
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
4
AN:
1454346
Hom.:
Cov.:
32
AF XY:
AC XY:
3
AN XY:
723038
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ExAC
?
AF:
AC:
1
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 | Feb 16, 2023 | The c.2380G>T (p.D794Y) alteration is located in exon 7 (coding exon 6) of the PLEKHM1 gene. This alteration results from a G to T substitution at nucleotide position 2380, causing the aspartic acid (D) at amino acid position 794 to be replaced by a tyrosine (Y). 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
Uncertain
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of helix (P = 0.0496);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at