Variant chr1-204228208-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000272203.8(PLEKHA6):c.2906T>C(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 (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

PLEKHA6
ENST00000272203.8 missense

Scores

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)

PLEKHA6 links:

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
PLEKHA6	NM_014935.5 linkuse as main transcript	c.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
PLEKHA6	ENST00000272203.8 linkuse as main transcript	c.2906T>C	p.Ile969Thr	missense_variant	21/23	1	NM_014935.5	ENSP00000272203	P2
PLEKHA6	ENST00000637508.1 linkuse as main transcript	c.3278T>C	p.Ile1093Thr	missense_variant	25/27	5		ENSP00000490182	A2
PLEKHA6	ENST00000414478.1 linkuse as main transcript	c.2966T>C	p.Ile989Thr	missense_variant	21/23	5		ENSP00000402046

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152138

Hom.:

Cov.:

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:

AN:

247614

Hom.:

AF XY:

0.0000299

AC XY:

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:

AN:

1457198

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

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:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

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.:

Bravo

AF:

0.0000945

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.00346

AC:

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 submitter

clinical testing

Ambry Genetics

Jan 18, 2023

The 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

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.021

T;T;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.81

T;T;T

M_CAP

Benign

0.0041

MetaRNN

Benign

0.032

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.33

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over