1-15718621-A-T

Position:

chr1-15718621-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_015164.4(PLEKHM2):c.461A>T(p.Asp154Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000083 in 1,325,524 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D154H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000052 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PLEKHM2
NM_015164.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.85

Variant links:

Genes affected

PLEKHM2 (HGNC:29131): (pleckstrin homology and RUN domain containing M2) This gene encodes a protein that binds the plus-end directed microtubule motor protein kinesin, together with the lysosomal GTPase Arl8, and is required for lysosomes to distribute away from the microtubule-organizing center. The encoded protein belongs to the multisubunit BLOC-one-related complex that regulates lysosome positioning. It binds a Salmonella effector protein called Salmonella induced filament A and is a critical host determinant in Salmonella pathogenesis. It has a domain architecture consisting of an N-terminal RPIP8, UNC-14, and NESCA (RUN) domain that binds kinesin-1 as well as the lysosomal GTPase Arl8, and a C-terminal pleckstrin homology domain that binds the Salmonella induced filament A effector protein. Naturally occurring mutations in this gene lead to abnormal localization of lysosomes, impaired autophagy flux and are associated with recessive dilated cardiomyopathy and left ventricular noncompaction. [provided by RefSeq, Feb 2017]

PLEKHM2 links:

PLEKHM2 (HGNC:):

PLEKHM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PLEKHM2	NM_015164.4 linkuse as main transcript	c.461A>T	p.Asp154Val	missense_variant	5/20	ENST00000375799.8	NP_055979.2
PLEKHM2	NM_001410755.1 linkuse as main transcript	c.461A>T	p.Asp154Val	missense_variant	5/19		NP_001397684.1
PLEKHM2	XM_017000757.1 linkuse as main transcript	c.500A>T	p.Asp167Val	missense_variant	5/20		XP_016856246.1
PLEKHM2	XM_017000758.1 linkuse as main transcript	c.500A>T	p.Asp167Val	missense_variant	5/19		XP_016856247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PLEKHM2	ENST00000375799.8 linkuse as main transcript	c.461A>T	p.Asp154Val	missense_variant	5/20	1	NM_015164.4	ENSP00000364956.3	Q8IWE5-1
PLEKHM2	ENST00000375793.2 linkuse as main transcript	c.461A>T	p.Asp154Val	missense_variant	5/19	5		ENSP00000364950.2	Q8IWE5-2
PLEKHM2	ENST00000642363.1 linkuse as main transcript	c.461A>T	p.Asp154Val	missense_variant	5/21			ENSP00000494591.1	A0A2R8Y575
PLEKHM2	ENST00000462455.1 linkuse as main transcript	n.369A>T		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes

AF:

0.0000523

AC:

AN:

133738

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000195

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000336

AC:

AN:

1191786

Hom.:

Cov.:

AF XY:

0.00000341

AC XY:

AN XY:

586644

show subpopulations

Gnomad4 AFR exome

AF:

0.000156

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000523

AC:

AN:

133738

Hom.:

Cov.:

AF XY:

0.0000784

AC XY:

AN XY:

63812

show subpopulations

Gnomad4 AFR

AF:

0.000195

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ExAC

AF:

0.00000859

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dilated Cardiomyopathy, Recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 154 of the PLEKHM2 protein (p.Asp154Val). This variant is present in population databases (rs764894986, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PLEKHM2-related conditions. ClinVar contains an entry for this variant (Variation ID: 478100). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-4.3

D;D;.

REVEL

Uncertain

0.31

Sift

Uncertain

0.013

D;D;.

Sift4G

Uncertain

0.0040

D;D;.

Polyphen

0.92

P;.;.

Vest4

0.64

MutPred

0.72

Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);

MVP

0.29

MPC

0.64

ClinPred

0.99

GERP RS

5.2

Varity_R

0.33

gMVP

0.49

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