17-45453472-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

(HGNC:):

ACMG classification

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 exomes AF: 0.00000488 AC: 1 AN: 204976 Hom.: 0 AF XY: 0.00000903 AC XY: 1 AN XY: 110780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000330

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000275 AC: 4 AN: 1454346 Hom.: 0 Cov.: 32 AF XY: 0.00000415 AC XY: 3 AN XY: 723038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000228

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.73	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.35		Gain of helix (P = 0.0496);
MVP		0.75
MPC		2.0
ClinPred		0.90	D
GERP RS		4.7
Varity_R		0.24
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs751751709; hg19: chr17-43530838; COSMIC: COSV101378640;