1-204228208-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014935.5(PLEKHA6):ā€‹c.2906T>Cā€‹(p.Ile969Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000516 in 1,609,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00014 ( 0 hom., cov: 33)
Exomes š‘“: 0.000042 ( 0 hom. )

Consequence

PLEKHA6
NM_014935.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46
Variant links:
Genes affected
PLEKHA6 (HGNC:17053): (pleckstrin homology domain containing A6)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.031707913).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PLEKHA6NM_014935.5 linkuse as main transcriptc.2906T>C p.Ile969Thr missense_variant 21/23 ENST00000272203.8 NP_055750.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PLEKHA6ENST00000272203.8 linkuse as main transcriptc.2906T>C p.Ile969Thr missense_variant 21/231 NM_014935.5 ENSP00000272203 P2
PLEKHA6ENST00000637508.1 linkuse as main transcriptc.3278T>C p.Ile1093Thr missense_variant 25/275 ENSP00000490182 A2
PLEKHA6ENST00000414478.1 linkuse as main transcriptc.2966T>C p.Ile989Thr missense_variant 21/235 ENSP00000402046

Frequencies

GnomAD3 genomes
AF:
0.000145
AC:
22
AN:
152138
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000785
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00116
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.0000363
AC:
9
AN:
247614
Hom.:
0
AF XY:
0.0000299
AC XY:
4
AN XY:
133770
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000878
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000110
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000668
GnomAD4 exome
AF:
0.0000419
AC:
61
AN:
1457198
Hom.:
0
Cov.:
31
AF XY:
0.0000331
AC XY:
24
AN XY:
724360
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000676
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000354
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000732
GnomAD4 genome
AF:
0.000145
AC:
22
AN:
152138
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000785
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00116
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00143
Alfa
AF:
0.000214
Hom.:
0
Bravo
AF:
0.0000945
ExAC
AF:
0.0000330
AC:
4
Asia WGS
AF:
0.00346
AC:
12
AN:
3478

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 GeneticsJan 18, 2023The c.2906T>C (p.I969T) alteration is located in exon 21 (coding exon 19) of the PLEKHA6 gene. This alteration results from a T to C substitution at nucleotide position 2906, causing the isoleucine (I) at amino acid position 969 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
0.070
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
18
DANN
Benign
0.86
DEOGEN2
Benign
0.021
T;T;.
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.34
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.81
T;T;T
M_CAP
Benign
0.0041
T
MetaRNN
Benign
0.032
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;.;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.24
N;.;N
REVEL
Benign
0.066
Sift
Benign
0.23
T;.;T
Sift4G
Benign
0.21
T;.;T
Polyphen
0.0
B;.;.
Vest4
0.22
MutPred
0.12
Gain of glycosylation at I969 (P = 0.0221);.;.;
MVP
0.043
MPC
0.13
ClinPred
0.023
T
GERP RS
2.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.040
gMVP
0.18

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: rs376064147; hg19: chr1-204197336; API