dbSNP rs941263363: PLEKHA8:p.Ile26Val (chr7-30045120-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001197026.2(PLEKHA8):c.76A>G(p.Ile26Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. I26M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PLEKHA8
NM_001197026.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.30

Publications

0 publications found

Variant links:

Genes affected

PLEKHA8 (HGNC:30037): (pleckstrin homology domain containing A8) Enables several functions, including ceramide binding activity; glycolipid transfer activity; and phosphatidylinositol-4-phosphate binding activity. Involved in ER to Golgi ceramide transport. Located in nucleoplasm and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

PLEKHA8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33037132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA8	NM_001197026.2 link	c.76A>G	p.Ile26Val	missense_variant	Exon 2 of 14	ENST00000449726.6	NP_001183955.1	Q96JA3-1A0A2P1JJM6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHA8	ENST00000449726.6 link	c.76A>G	p.Ile26Val	missense_variant	Exon 2 of 14	1	NM_001197026.2	ENSP00000397947.1		Q96JA3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458316

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725526

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33168

American (AMR)

AF:

0.00

AC:

AN:

44102

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25988

East Asian (EAS)

AF:

0.00

AC:

AN:

39522

South Asian (SAS)

AF:

0.00

AC:

AN:

85706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110498

Other (OTH)

AF:

0.00

AC:

AN:

60216

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 28, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.76A>G (p.I26V) alteration is located in exon 2 (coding exon 2) of the PLEKHA8 gene. This alteration results from a A to G substitution at nucleotide position 76, causing the isoleucine (I) at amino acid position 26 to be replaced by a valine (V). 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

0.11

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.;.;.;T;T

Eigen

Benign

-0.24

Eigen_PC

Benign

0.0063

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

T;T;T;T;T;.

M_CAP

Benign

0.014

MetaRNN

Benign

0.33

T;T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.035

N;.;N;N;.;.

PhyloP100

6.3

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.080

N;.;N;N;N;N

REVEL

Benign

0.22

Sift

Benign

0.24

T;.;T;T;T;T

Sift4G

Benign

0.34

T;T;T;T;T;T

Polyphen

0.15, 0.0050

.;.;B;B;.;.

Vest4

0.17

MutPred

0.49

.;.;.;.;.;Gain of sheet (P = 0.1451);

MVP

0.78

MPC

0.28

ClinPred

0.68

GERP RS

5.3

Varity_R

0.10

gMVP

0.095

Mutation Taster

=87/13

polymorphism

(source)

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

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rs941263363

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over