chr2-207861117-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001080475.3(PLEKHM3):ā€‹c.2096T>Cā€‹(p.Ile699Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I699M) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

PLEKHM3
NM_001080475.3 missense

Scores

3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.17
Variant links:
Genes affected
PLEKHM3 (HGNC:34006): (pleckstrin homology domain containing M3) Predicted to enable metal ion binding activity. Predicted to be involved in myoblast differentiation. Predicted to be located in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.16293651).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PLEKHM3NM_001080475.3 linkuse as main transcriptc.2096T>C p.Ile699Thr missense_variant 7/8 ENST00000427836.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PLEKHM3ENST00000427836.8 linkuse as main transcriptc.2096T>C p.Ile699Thr missense_variant 7/85 NM_001080475.3 P1Q6ZWE6-1
PLEKHM3ENST00000447645.5 linkuse as main transcriptc.1352T>C p.Ile451Thr missense_variant 5/72

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460782
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
726628
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 27, 2023The c.2096T>C (p.I699T) alteration is located in exon 7 (coding exon 6) of the PLEKHM3 gene. This alteration results from a T to C substitution at nucleotide position 2096, causing the isoleucine (I) at amino acid position 699 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Uncertain
0.041
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
19
DANN
Benign
0.90
DEOGEN2
Benign
0.0015
T
Eigen
Benign
-0.042
Eigen_PC
Benign
0.11
FATHMM_MKL
Benign
0.74
D
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.16
T
MetaSVM
Benign
-0.44
T
MutationAssessor
Benign
-0.34
N
MutationTaster
Benign
0.63
D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
1.7
N
REVEL
Uncertain
0.35
Sift
Benign
0.56
T
Sift4G
Benign
1.0
T
Polyphen
0.61
P
Vest4
0.48
MutPred
0.29
Gain of disorder (P = 0.0278);
MVP
0.44
MPC
0.13
ClinPred
0.64
D
GERP RS
5.1
Varity_R
0.13
gMVP
0.37

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: rs1296865966; hg19: chr2-208725841; API