rs3946526

Variant names:

• chr17-45464290-C-T
• rs3946526
• NM_014798.3:c.1308+3919G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014798.3(PLEKHM1):​c.1308+3919G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 152,186 control chromosomes in the GnomAD database, including 1,550 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 0.12 (1550 hom., cov: 32)
• Consequence: PLEKHM1 NM_014798.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.167
• Publications: 23 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

ENSG00000236234 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• 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.1308+3919G>A		intron	N/A	NP_055613.1
	PLEKHM1	NM_001352825.2		c.1308+3919G>A		intron	N/A	NP_001339754.1
	PLEKHM1	NR_027774.2		n.1171+3919G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM1	ENST00000430334.8	TSL:1 MANE Select	c.1308+3919G>A		intron	N/A	ENSP00000389913.3
	PLEKHM1	ENST00000581448.5	TSL:1	n.924-5851G>A		intron	N/A	ENSP00000462160.1
	PLEKHM1	ENST00000446609.7	TSL:5	c.1308+3919G>A		intron	N/A	ENSP00000394344.3

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18732 AN: 152068 Hom.: 1552 Cov.: 32

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0596

Gnomad FIN AF: 0.0417

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.170

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.123 AC: 18722 AN: 152186 Hom.: 1550 Cov.: 32 AF XY: 0.115 AC XY: 8579 AN XY: 74402

African (AFR) AF: 0.0433 AC: 1799 AN: 41504

American (AMR) AF: 0.167 AC: 2548 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 729 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5186

South Asian (SAS) AF: 0.0594 AC: 286 AN: 4814

European-Finnish (FIN) AF: 0.0417 AC: 442 AN: 10612

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

European-Non Finnish (NFE) AF: 0.180 AC: 12219 AN: 68004

Other (OTH) AF: 0.167 AC: 352 AN: 2110

Alfa AF: 0.132 Hom.: 255

Bravo AF: 0.130

Asia WGS AF: 0.0260 AC: 92 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.6
DANN	Benign	0.25
PhyloP100		0.17
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: rs3946526; hg19: chr17-43541656;