17-45453712-G-T

Variant names:

• chr17-45453712-G-T
• rs559224144
• NM_014798.3:c.2140C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R714C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PLEKHM1 NM_014798.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.51
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive osteopetrosis 6

  Inheritance: AR Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, ClinGen, Orphanet
• osteopetrosis, autosomal dominant 3

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000236234 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-45453712-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 560304.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3061427).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014798.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM1	NM_014798.3	MANE Select	c.2140C>A	p.Arg714Ser	missense	Exon 7 of 12	NP_055613.1	Q9Y4G2
	PLEKHM1	NM_001352825.2		c.2140C>A	p.Arg714Ser	missense	Exon 7 of 7	NP_001339754.1	A0A8V8TPW0
	PLEKHM1	NR_027774.2		n.2003C>A		non_coding_transcript_exon	Exon 6 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM1	ENST00000430334.8	TSL:1 MANE Select	c.2140C>A	p.Arg714Ser	missense	Exon 7 of 12	ENSP00000389913.3	Q9Y4G2
	PLEKHM1	ENST00000580205.1	TSL:1	n.1611C>A		non_coding_transcript_exon	Exon 2 of 2
	PLEKHM1	ENST00000581448.5	TSL:1	n.*747C>A		non_coding_transcript_exon	Exon 6 of 11	ENSP00000462160.1	J3KRU0

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.5
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

Other links and lift over

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