Variant 17-45453505-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_014798.3(PLEKHM1):c.2347G>A(p.Ala783Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000167 in 1,609,622 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

PLEKHM1
NM_014798.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.47

Variant links:

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]

PLEKHM1 links:

(HGNC:):

links:

Genome browser will be placed here

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 linkuse as main transcript	c.2347G>A	p.Ala783Thr	missense_variant	7/12	ENST00000430334.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM1	ENST00000430334.8 linkuse as main transcript	c.2347G>A	p.Ala783Thr	missense_variant	7/12	1	NM_014798.3	P1
	ENST00000433601.1 linkuse as main transcript	n.245+417C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000856

AC:

AN:

151922

Hom.:

Cov.:

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000522

AC:

AN:

210610

Hom.:

AF XY:

0.0000698

AC XY:

AN XY:

114602

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000121

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000176

AC:

256

AN:

1457700

Hom.:

Cov.:

AF XY:

0.000185

AC XY:

134

AN XY:

724888

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:

0.000193

Gnomad4 OTH exome

AF:

0.000698

GnomAD4 genome

AF:

0.0000856

AC:

AN:

151922

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74220

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:

0.000191

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000982

ExAC

AF:

0.00000827

AC:

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

Dec 15, 2022

The c.2347G>A (p.A783T) alteration is located in exon 7 (coding exon 6) of the PLEKHM1 gene. This alteration results from a G to A substitution at nucleotide position 2347, causing the alanine (A) at amino acid position 783 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.39

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.069

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.93

M_CAP

Benign

0.052

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.95

N;N

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.5

REVEL

Benign

0.12

Sift

Benign

0.068

Sift4G

Uncertain

0.017

Polyphen

0.95

Vest4

0.41

MVP

0.71

MPC

1.4

ClinPred

0.31

GERP RS

4.7

Varity_R

0.081

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over