17-45439372-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014798.3(PLEKHM1):c.3059+105T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.712 in 1,295,258 control chromosomes in the GnomAD database, including 331,301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.73 (40656 hom., cov: 33)
  • Exomes 𝑓: 0.71 (290645 hom.)
• Consequence: PLEKHM1 NM_014798.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.32

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-45439372-A-C is Benign according to our data. Variant chr17-45439372-A-C is described in ClinVar as [Benign]. Clinvar id is 1282226.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHM1	NM_014798.3	c.3059+105T>G		intron_variant		ENST00000430334.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM1	ENST00000430334.8	c.3059+105T>G		intron_variant		1	NM_014798.3	P1

Frequencies

GnomAD3 genomes AF: 0.726 AC: 110419 AN: 152046 Hom.: 40614 Cov.: 33

Gnomad AFR AF: 0.831

Gnomad AMI AF: 0.810

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.691

GnomAD4 exome AF: 0.710 AC: 811693 AN: 1143094 Hom.: 290645 AF XY: 0.707 AC XY: 410366 AN XY: 580192

Gnomad4 AFR exome AF: 0.830

Gnomad4 AMR exome AF: 0.636

Gnomad4 ASJ exome AF: 0.674

Gnomad4 EAS exome AF: 0.484

Gnomad4 SAS exome AF: 0.666

Gnomad4 FIN exome AF: 0.659

Gnomad4 NFE exome AF: 0.729

Gnomad4 OTH exome AF: 0.702

GnomAD4 genome AF: 0.726 AC: 110516 AN: 152164 Hom.: 40656 Cov.: 33 AF XY: 0.719 AC XY: 53457 AN XY: 74386

Gnomad4 AFR AF: 0.831

Gnomad4 AMR AF: 0.675

Gnomad4 ASJ AF: 0.670

Gnomad4 EAS AF: 0.454

Gnomad4 SAS AF: 0.657

Gnomad4 FIN AF: 0.649

Gnomad4 NFE AF: 0.715

Gnomad4 OTH AF: 0.690

Alfa AF: 0.723 Hom.: 8563

Bravo AF: 0.730

Asia WGS AF: 0.557 AC: 1938 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.12
Dann	Benign	0.56

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: rs1317946; hg19: chr17-43516738; COSMIC: COSV69599045; COSMIC: COSV69599045;