Genetic Variant NM_001197026.2:c.836T>C (chr7-30054748-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001197026.2(PLEKHA8):c.836T>C(p.Leu279Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PLEKHA8
NM_001197026.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.593

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.091810584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA8	NM_001197026.2 link	c.836T>C	p.Leu279Pro	missense_variant	Exon 8 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.836T>C	p.Leu279Pro	missense_variant	Exon 8 of 14	1	NM_001197026.2	ENSP00000397947.1		Q96JA3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1451204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722150

African (AFR)

AF:

0.00

AC:

AN:

33106

American (AMR)

AF:

0.00

AC:

AN:

43250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25946

East Asian (EAS)

AF:

0.00

AC:

AN:

39184

South Asian (SAS)

AF:

0.00

AC:

AN:

84980

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105872

Other (OTH)

AF:

0.00

AC:

AN:

59906

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 11, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.836T>C (p.L279P) alteration is located in exon 8 (coding exon 8) of the PLEKHA8 gene. This alteration results from a T to C substitution at nucleotide position 836, causing the leucine (L) at amino acid position 279 to be replaced by a proline (P). 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

0.068

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.0087

T;.;.;.;T;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.61

T;T;T;T;T;.

M_CAP

Benign

0.0038

MetaRNN

Benign

0.092

T;T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.2

L;.;L;L;.;.

PhyloP100

0.59

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.17

N;.;N;N;N;N

REVEL

Benign

0.097

Sift

Benign

0.23

T;.;T;T;T;T

Sift4G

Benign

0.30

T;T;T;T;T;T

Polyphen

0.31

B;.;B;B;.;.

Vest4

0.33

MutPred

0.36

Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);.;

MVP

0.36

MPC

0.48

ClinPred

0.22

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.054

gMVP

0.44

Mutation Taster

=85/15

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over