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17-45439623-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014798.3(PLEKHM1):c.2913G>A(p.Gly971=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00453 in 1,613,956 control chromosomes in the GnomAD database, including 291 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 159 hom., cov: 33)
Exomes 𝑓: 0.0023 ( 132 hom. )

Consequence

PLEKHM1
NM_014798.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.858
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.73).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-45439623-C-T is Benign according to our data. Variant chr17-45439623-C-T is described in ClinVar as [Benign]. Clinvar id is 1291719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.858 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0865 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PLEKHM1NM_014798.3 linkuse as main transcriptc.2913G>A p.Gly971= synonymous_variant 11/12 ENST00000430334.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PLEKHM1ENST00000430334.8 linkuse as main transcriptc.2913G>A p.Gly971= synonymous_variant 11/121 NM_014798.3 P1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0255
AC:
3878
AN:
152078
Hom.:
160
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0891
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00916
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.0173
GnomAD3 exomes
AF:
0.00646
AC:
1624
AN:
251394
Hom.:
68
AF XY:
0.00495
AC XY:
673
AN XY:
135894
show subpopulations
Gnomad AFR exome
AF:
0.0905
Gnomad AMR exome
AF:
0.00373
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000879
Gnomad OTH exome
AF:
0.00212
GnomAD4 exome
AF:
0.00235
AC:
3434
AN:
1461760
Hom.:
132
Cov.:
32
AF XY:
0.00205
AC XY:
1490
AN XY:
727174
show subpopulations
Gnomad4 AFR exome
AF:
0.0849
Gnomad4 AMR exome
AF:
0.00436
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000928
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000576
Gnomad4 OTH exome
AF:
0.00507
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0255
AC:
3879
AN:
152196
Hom.:
159
Cov.:
33
AF XY:
0.0246
AC XY:
1830
AN XY:
74414
show subpopulations
Gnomad4 AFR
AF:
0.0889
Gnomad4 AMR
AF:
0.00915
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.0171
Alfa
AF:
0.0164
Hom.:
42
Bravo
AF:
0.0287
Asia WGS
AF:
0.00577
AC:
20
AN:
3478
EpiCase
AF:
0.000218
EpiControl
AF:
0.000237

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Increased bone mineral density Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJan 13, 2021- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxJun 10, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.73
Cadd
Benign
0.36
Dann
Benign
0.87

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs73984399; hg19: chr17-43516989; API