17-45439373-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.3059+104C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,313,518 control chromosomes in the GnomAD database, including 18,185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1583 hom., cov: 33)
  • Exomes 𝑓: 0.16 (16602 hom.)
• Consequence: PLEKHM1 NM_014798.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.604

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=-0.81).
• BP6: Variant 17-45439373-G-A is Benign according to our data. Variant chr17-45439373-G-A is described in ClinVar as [Benign]. Clinvar id is 1251543.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHM1	NM_014798.3	c.3059+104C>T		intron_variant		ENST00000430334.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM1	ENST00000430334.8	c.3059+104C>T		intron_variant		1	NM_014798.3	P1

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19438 AN: 152152 Hom.: 1585 Cov.: 33

Gnomad AFR AF: 0.0597

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0607

Gnomad FIN AF: 0.0415

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.173

GnomAD4 exome AF: 0.156 AC: 180922 AN: 1161248 Hom.: 16602 AF XY: 0.154 AC XY: 90628 AN XY: 589282

Gnomad4 AFR exome AF: 0.0609

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.221

Gnomad4 EAS exome AF: 0.00100

Gnomad4 SAS exome AF: 0.0625

Gnomad4 FIN exome AF: 0.0467

Gnomad4 NFE exome AF: 0.181

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.128 AC: 19435 AN: 152270 Hom.: 1583 Cov.: 33 AF XY: 0.120 AC XY: 8916 AN XY: 74448

Gnomad4 AFR AF: 0.0598

Gnomad4 AMR AF: 0.168

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0605

Gnomad4 FIN AF: 0.0415

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.170

Alfa AF: 0.0255 Hom.: 12

Bravo AF: 0.136

Asia WGS AF: 0.0270 AC: 96 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	-0.81
Cadd	Benign	1.9
Dann	Benign	0.38

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: rs35591873; hg19: chr17-43516739;