17-45464468-C-T

Variant names:

• chr17-45464468-C-T
• rs2078200
• NM_014798.3:c.1308+3741G>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+3741G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.65 in 151,932 control chromosomes in the GnomAD database, including 32,501 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 0.65 (32501 hom., cov: 31)
• Consequence: PLEKHM1 NM_014798.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.96
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.709 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM1	NM_014798.3	MANE Select	c.1308+3741G>A		intron	N/A	NP_055613.1
	PLEKHM1	NM_001352825.2		c.1308+3741G>A		intron	N/A	NP_001339754.1
	PLEKHM1	NR_027774.2		n.1171+3741G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHM1	ENST00000430334.8	TSL:1 MANE Select	c.1308+3741G>A		intron	N/A	ENSP00000389913.3
	PLEKHM1	ENST00000581448.5	TSL:1	n.924-6029G>A		intron	N/A	ENSP00000462160.1
	PLEKHM1	ENST00000446609.7	TSL:5	c.1308+3741G>A		intron	N/A	ENSP00000394344.3

Frequencies

GnomAD3 genomes AF: 0.650 AC: 98697 AN: 151814 Hom.: 32505 Cov.: 31

Gnomad AFR AF: 0.568

Gnomad AMI AF: 0.810

Gnomad AMR AF: 0.645

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.657

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.714

Gnomad OTH AF: 0.636

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

GnomAD4 genome AF: 0.650 AC: 98727 AN: 151932 Hom.: 32501 Cov.: 31 AF XY: 0.644 AC XY: 47817 AN XY: 74234

African (AFR) AF: 0.567 AC: 23491 AN: 41434

American (AMR) AF: 0.645 AC: 9841 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2264 AN: 3460

East Asian (EAS) AF: 0.453 AC: 2337 AN: 5158

South Asian (SAS) AF: 0.656 AC: 3158 AN: 4814

European-Finnish (FIN) AF: 0.649 AC: 6854 AN: 10566

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.714 AC: 48527 AN: 67930

Other (OTH) AF: 0.635 AC: 1333 AN: 2098

Alfa AF: 0.662 Hom.: 4567

Bravo AF: 0.642

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.0020
DANN	Benign	0.47
PhyloP100		-4.0
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: rs2078200; hg19: chr17-43541834;