Genetic Variant PLEKHA8:p.Ser13Asn (chr7-30028800-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001197026.2(PLEKHA8):c.38G>A(p.Ser13Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000179 in 1,117,818 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

PLEKHA8
NM_001197026.2 missense, splice_region

Scores

Splicing: ADA: 0.9073

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.56

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA8	NM_001197026.2 link	c.38G>A	p.Ser13Asn	missense_variant, splice_region_variant	Exon 1 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.38G>A	p.Ser13Asn	missense_variant, splice_region_variant	Exon 1 of 14	1	NM_001197026.2	ENSP00000397947.1		Q96JA3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000179

AC:

AN:

1117818

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

530870

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23584

American (AMR)

AF:

0.00

AC:

AN:

10416

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14760

East Asian (EAS)

AF:

0.00

AC:

AN:

27660

South Asian (SAS)

AF:

0.00

AC:

AN:

21250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36460

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4576

European-Non Finnish (NFE)

AF:

0.00000214

AC:

AN:

934210

Other (OTH)

AF:

0.00

AC:

AN:

44902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.38G>A (p.S13N) alteration is located in exon 1 (coding exon 1) of the PLEKHA8 gene. This alteration results from a G to A substitution at nucleotide position 38, causing the serine (S) at amino acid position 13 to be replaced by an asparagine (N). 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

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.052

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.;.;.;T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.71

T;T;T;T;T;.

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.45

T;T;T;T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Benign

1.6

L;.;L;L;.;.

PhyloP100

6.6

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.4

N;.;N;N;N;N

REVEL

Benign

0.27

Sift

Uncertain

0.020

D;.;D;T;D;T

Sift4G

Benign

0.13

T;T;T;T;T;T

Polyphen

1.0, 0.28

.;.;D;B;.;.

Vest4

0.45

MutPred

0.43

.;.;.;.;.;Gain of sheet (P = 0.0827);

MVP

0.86

MPC

0.61

ClinPred

0.97

GERP RS

5.4

PromoterAI

0.033

Neutral

(source)

Varity_R

0.42

gMVP

0.12

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.91

dbscSNV1_RF

Pathogenic

0.79

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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7-30028800-G-A

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