17-45436075-C-T

Variant names:

• chr17-45436075-C-T
• rs11012
• NM_014798.3:c.*1783G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_014798.3(PLEKHM1):​c.*1783G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 456,526 control chromosomes in the GnomAD database, including 5,159 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1618 hom., cov: 33)
  • Exomes 𝑓: 0.14 (3541 hom.)
• Consequence: PLEKHM1 NM_014798.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.208
• Publications: 96 publications found

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]

PLEKHM1 Gene-Disease associations (from GenCC):

• autosomal recessive osteopetrosis 6

  Inheritance: AR Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, ClinGen
• osteopetrosis, autosomal dominant 3

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.103).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014798.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM1	NM_014798.3	MANE Select	c.*1783G>A		3_prime_UTR	Exon 12 of 12	NP_055613.1
	PLEKHM1	NR_027774.2		n.4817G>A		non_coding_transcript_exon	Exon 11 of 11
	PLEKHM1	NR_027782.2		n.4680G>A		non_coding_transcript_exon	Exon 11 of 11

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM1	ENST00000430334.8	TSL:1 MANE Select	c.*1783G>A		3_prime_UTR	Exon 12 of 12	ENSP00000389913.3
	PLEKHM1	ENST00000579197.5	TSL:2	n.*4514G>A		non_coding_transcript_exon	Exon 11 of 11	ENSP00000462282.1
	PLEKHM1	ENST00000580404.5	TSL:5	n.2456G>A		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19812 AN: 152184 Hom.: 1620 Cov.: 33

Gnomad AFR AF: 0.0681

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0602

Gnomad FIN AF: 0.0416

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.177

GnomAD2 exomes AF: 0.130 AC: 17783 AN: 136934 AF XY: 0.130

Gnomad AFR exome AF: 0.0711

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.223

Gnomad EAS exome AF: 0.000571

Gnomad FIN exome AF: 0.0405

Gnomad NFE exome AF: 0.186

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.136 AC: 41237 AN: 304224 Hom.: 3541 Cov.: 0 AF XY: 0.131 AC XY: 22727 AN XY: 173222

African (AFR) AF: 0.0772 AC: 666 AN: 8628

American (AMR) AF: 0.118 AC: 3224 AN: 27282

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 2400 AN: 10790

East Asian (EAS) AF: 0.000543 AC: 5 AN: 9210

South Asian (SAS) AF: 0.0650 AC: 3886 AN: 59744

European-Finnish (FIN) AF: 0.0473 AC: 596 AN: 12612

Middle Eastern (MID) AF: 0.199 AC: 554 AN: 2782

European-Non Finnish (NFE) AF: 0.175 AC: 27849 AN: 158944

Other (OTH) AF: 0.145 AC: 2057 AN: 14232

GnomAD4 genome AF: 0.130 AC: 19809 AN: 152302 Hom.: 1618 Cov.: 33 AF XY: 0.122 AC XY: 9082 AN XY: 74474

African (AFR) AF: 0.0681 AC: 2832 AN: 41574

American (AMR) AF: 0.168 AC: 2576 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 730 AN: 3472

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5190

South Asian (SAS) AF: 0.0600 AC: 290 AN: 4830

European-Finnish (FIN) AF: 0.0416 AC: 442 AN: 10614

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12223 AN: 68002

Other (OTH) AF: 0.174 AC: 368 AN: 2116

Alfa AF: 0.167 Hom.: 5430

Bravo AF: 0.139

Asia WGS AF: 0.0270 AC: 97 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.6
DANN	Benign	0.47
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11012; hg19: chr17-43513441; COSMIC: COSV51818174; COSMIC: COSV51818174;