10-113766687-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001395068.1(PLEKHS1):​c.193C>T​(p.His65Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H65Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

PLEKHS1
NM_001395068.1 missense

Scores

3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.297
Variant links:
Genes affected
PLEKHS1 (HGNC:26285): (pleckstrin homology domain containing S1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16031173).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLEKHS1NM_001395068.1 linkc.193C>T p.His65Tyr missense_variant Exon 4 of 13 ENST00000694986.1 NP_001381997.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PLEKHS1ENST00000694986.1 linkc.193C>T p.His65Tyr missense_variant Exon 4 of 13 NM_001395068.1 ENSP00000511629.1 A0A8Q3WKA6

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000805
AC:
2
AN:
248564
Hom.:
0
AF XY:
0.00000745
AC XY:
1
AN XY:
134156
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000338
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.00000480
AC:
7
AN:
1459346
Hom.:
0
Cov.:
31
AF XY:
0.00000551
AC XY:
4
AN XY:
725732
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:
0.0000586
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 22, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.175C>T (p.H59Y) alteration is located in exon 3 (coding exon 3) of the PLEKHS1 gene. This alteration results from a C to T substitution at nucleotide position 175, causing the histidine (H) at amino acid position 59 to be replaced by a tyrosine (Y). 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
Benign
-0.26
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
14
DANN
Uncertain
0.99
Eigen
Benign
-0.094
Eigen_PC
Benign
-0.23
FATHMM_MKL
Benign
0.48
N
LIST_S2
Benign
0.55
.;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.16
T;T
MetaSVM
Benign
-1.1
T
PrimateAI
Benign
0.30
T
PROVEAN
Uncertain
-3.0
D;D
REVEL
Benign
0.095
Sift
Benign
0.031
D;T
Sift4G
Uncertain
0.0090
D;D
Vest4
0.27
MutPred
0.32
.;Loss of disorder (P = 0.0543);
MVP
0.072
MPC
0.22
ClinPred
0.66
D
GERP RS
2.2
gMVP
0.18

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs759372909; hg19: chr10-115526446; API