17-45445409-TTGTG-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_014798.3(PLEKHM1):c.2837+57_2837+60del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,407,996 control chromosomes in the GnomAD database, including 15,833 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1431 hom., cov: 30)
  • Exomes 𝑓: 0.16 (14402 hom.)
• Consequence: PLEKHM1 NM_014798.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.01

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 -10 ACMG points.

• BP6: Variant 17-45445409-TTGTG-T is Benign according to our data. Variant chr17-45445409-TTGTG-T is described in ClinVar as [Benign]. Clinvar id is 1259474.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHM1	NM_014798.3	c.2837+57_2837+60del		intron_variant		ENST00000430334.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM1	ENST00000430334.8	c.2837+57_2837+60del		intron_variant		1	NM_014798.3	P1

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19215 AN: 151718 Hom.: 1433 Cov.: 30

Gnomad AFR AF: 0.0596

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0600

Gnomad FIN AF: 0.0413

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.174

GnomAD4 exome AF: 0.157 AC: 197165 AN: 1256160 Hom.: 14402 AF XY: 0.155 AC XY: 98015 AN XY: 633256

Gnomad4 AFR exome AF: 0.0589

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.219

Gnomad4 EAS exome AF: 0.000730

Gnomad4 SAS exome AF: 0.0630

Gnomad4 FIN exome AF: 0.0467

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.151

GnomAD4 genome AF: 0.127 AC: 19212 AN: 151836 Hom.: 1431 Cov.: 30 AF XY: 0.119 AC XY: 8835 AN XY: 74280

Gnomad4 AFR AF: 0.0596

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.208

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0599

Gnomad4 FIN AF: 0.0413

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.171

Alfa AF: 0.138 Hom.: 191

Bravo AF: 0.135

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

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: rs55793421; hg19: chr17-43522775;