17-45453184-G-A

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.2497+171C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 661,858 control chromosomes in the GnomAD database, including 88,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.46 (17160 hom., cov: 30)
  • Exomes 𝑓: 0.52 (71522 hom.)
• Consequence: PLEKHM1 NM_014798.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.36

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-45453184-G-A is Benign according to our data. Variant chr17-45453184-G-A is described in ClinVar as [Benign]. Clinvar id is 1284230.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHM1	NM_014798.3	c.2497+171C>T		intron_variant		ENST00000430334.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM1	ENST00000430334.8	c.2497+171C>T		intron_variant		1	NM_014798.3	P1
	ENST00000433601.1	n.245+96G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70489 AN: 151666 Hom.: 17159 Cov.: 30

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.506

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.421

GnomAD4 exome AF: 0.525 AC: 267743 AN: 510074 Hom.: 71522 Cov.: 5 AF XY: 0.530 AC XY: 143487 AN XY: 270698

Gnomad4 AFR exome AF: 0.320

Gnomad4 AMR exome AF: 0.476

Gnomad4 ASJ exome AF: 0.437

Gnomad4 EAS exome AF: 0.488

Gnomad4 SAS exome AF: 0.600

Gnomad4 FIN exome AF: 0.614

Gnomad4 NFE exome AF: 0.529

Gnomad4 OTH exome AF: 0.495

GnomAD4 genome AF: 0.465 AC: 70521 AN: 151784 Hom.: 17160 Cov.: 30 AF XY: 0.468 AC XY: 34700 AN XY: 74174

Gnomad4 AFR AF: 0.317

Gnomad4 AMR AF: 0.451

Gnomad4 ASJ AF: 0.443

Gnomad4 EAS AF: 0.450

Gnomad4 SAS AF: 0.594

Gnomad4 FIN AF: 0.605

Gnomad4 NFE AF: 0.530

Gnomad4 OTH AF: 0.424

Alfa AF: 0.504 Hom.: 3843

Bravo AF: 0.441

Asia WGS AF: 0.498 AC: 1724 AN: 3468

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	-0.90
Cadd	Benign	0.40
Dann	Benign	0.63

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: rs56278545; hg19: chr17-43530550; COSMIC: COSV69598994;