17-45437588-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.*270C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 650,556 control chromosomes in the GnomAD database, including 7,715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1582 hom., cov: 31)
  • Exomes 𝑓: 0.14 (6133 hom.)
• Consequence: PLEKHM1 NM_014798.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0370

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 17-45437588-G-A is Benign according to our data. Variant chr17-45437588-G-A is described in ClinVar as [Benign]. Clinvar id is 1254078.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.*270C>T		3_prime_UTR_variant	12/12	ENST00000430334.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHM1	ENST00000430334.8	c.*270C>T		3_prime_UTR_variant	12/12	1	NM_014798.3	P1

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19397 AN: 151872 Hom.: 1584 Cov.: 31

Gnomad AFR AF: 0.0594

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0602

Gnomad FIN AF: 0.0417

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.174

GnomAD3 exomes AF: 0.127 AC: 16549 AN: 130612 Hom.: 1400 AF XY: 0.127 AC XY: 9035 AN XY: 71292

Gnomad AFR exome AF: 0.0600

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.223

Gnomad EAS exome AF: 0.000575

Gnomad SAS exome AF: 0.0620

Gnomad FIN exome AF: 0.0405

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.140 AC: 69654 AN: 498566 Hom.: 6133 Cov.: 0 AF XY: 0.137 AC XY: 37247 AN XY: 271330

Gnomad4 AFR exome AF: 0.0648

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.000580

Gnomad4 SAS exome AF: 0.0643

Gnomad4 FIN exome AF: 0.0468

Gnomad4 NFE exome AF: 0.178

Gnomad4 OTH exome AF: 0.152

GnomAD4 genome AF: 0.128 AC: 19393 AN: 151990 Hom.: 1582 Cov.: 31 AF XY: 0.120 AC XY: 8893 AN XY: 74296

Gnomad4 AFR AF: 0.0595

Gnomad4 AMR AF: 0.168

Gnomad4 ASJ AF: 0.210

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0598

Gnomad4 FIN AF: 0.0417

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.172

Alfa AF: 0.109 Hom.: 229

Bravo AF: 0.136

Asia WGS AF: 0.0270 AC: 94 AN: 3476

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	6.8
Dann	Benign	0.74

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: rs62064655; hg19: chr17-43514954;