17-45453712-G-T

Position:

• chr17-45453712-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_014798.3(PLEKHM1):​c.2140C>A​(p.Arg714Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PLEKHM1 NM_014798.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.51

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PLEKHM1. . Gene score misZ 1.182 (greater than the threshold 3.09). Trascript score misZ 4.3808 (greater than threshold 3.09). GenCC has associacion of gene with osteopetrosis, autosomal dominant 3, autosomal recessive osteopetrosis 6.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3061427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHM1	NM_014798.3	c.2140C>A	p.Arg714Ser	missense_variant	7/12	ENST00000430334.8	NP_055613.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHM1	ENST00000430334.8	c.2140C>A	p.Arg714Ser	missense_variant	7/12	1	NM_014798.3	ENSP00000389913	P1
	ENST00000433601.1	n.245+624G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.93	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.12
Sift	Benign	0.035	D
Sift4G	Uncertain	0.030	D
Polyphen		0.85	P
Vest4		0.37
MutPred		0.43		Gain of ubiquitination at K711 (P = 0.0356);
MVP		0.67
MPC		1.6
ClinPred		0.79	D
GERP RS		3.9
Varity_R		0.20
gMVP		0.62

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: rs559224144; hg19: chr17-43531078; COSMIC: COSV101378777;