17-45437861-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_014798.3(PLEKHM1):c.3168C>T(p.Ala1056=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,613,232 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (5 hom.)
• Consequence: PLEKHM1 NM_014798.3 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:2
• Conservation: PhyloP100: 1.50

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-45437861-G-A is Benign according to our data. Variant chr17-45437861-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1285181.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-45437861-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.5 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHM1	NM_014798.3	c.3168C>T	p.Ala1056=	synonymous_variant	12/12	ENST00000430334.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM1	ENST00000430334.8	c.3168C>T	p.Ala1056=	synonymous_variant	12/12	1	NM_014798.3	P1

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 156 AN: 152276 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00149 AC: 375 AN: 251064 Hom.: 1 AF XY: 0.00160 AC XY: 217 AN XY: 135864

Gnomad AFR exome AF: 0.000679

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00284

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00221 AC: 3223 AN: 1460838 Hom.: 5 Cov.: 31 AF XY: 0.00214 AC XY: 1554 AN XY: 726820

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000940

Gnomad4 NFE exome AF: 0.00274

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00102 AC: 156 AN: 152394 Hom.: 0 Cov.: 32 AF XY: 0.000778 AC XY: 58 AN XY: 74524

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00181

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00172 Hom.: 0

Bravo AF: 0.00106

EpiCase AF: 0.00104

EpiControl AF: 0.00284

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	4.2
Dann	Benign	0.71

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

Other links and lift over

dbSNP: rs116886592; hg19: chr17-43515227;