rs11012

Positions:

• chr17-45436075-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong 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

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• 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	Protein	UniProt
PLEKHM1	NM_014798.3	c.*1783G>A		3_prime_UTR_variant	12/12	ENST00000430334.8	NP_055613.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHM1	ENST00000430334.8	c.*1783G>A		3_prime_UTR_variant	12/12	1	NM_014798.3	ENSP00000389913	P1
PLEKHM1	ENST00000580404.5	n.2456G>A		non_coding_transcript_exon_variant	5/5	5
PLEKHM1	ENST00000579197.5	c.*4514G>A		3_prime_UTR_variant, NMD_transcript_variant	11/11	2		ENSP00000462282

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

GnomAD3 exomes AF: 0.130 AC: 17783 AN: 136934 Hom.: 1522 AF XY: 0.130 AC XY: 9647 AN XY: 74364

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 SAS exome AF: 0.0622

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

Gnomad4 AFR exome AF: 0.0772

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.222

Gnomad4 EAS exome AF: 0.000543

Gnomad4 SAS exome AF: 0.0650

Gnomad4 FIN exome AF: 0.0473

Gnomad4 NFE exome AF: 0.175

Gnomad4 OTH exome AF: 0.145

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

Gnomad4 AFR AF: 0.0681

Gnomad4 AMR AF: 0.168

Gnomad4 ASJ AF: 0.210

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0600

Gnomad4 FIN AF: 0.0416

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.174

Alfa AF: 0.182 Hom.: 3385

Bravo AF: 0.139

Asia WGS AF: 0.0270 AC: 97 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.6
DANN	Benign	0.47

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