NM_001197026.2:c.752A>G

Variant names:

• chr7-30052822-A-G
• NM_001197026.2:c.752A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001197026.2(PLEKHA8):​c.752A>G​(p.Asp251Gly) 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. 15/21 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)
• Consequence: PLEKHA8 NM_001197026.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17
• Publications: 0 publications found

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]

ACMG classification

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=0.0690369).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA8	NM_001197026.2	c.752A>G	p.Asp251Gly	missense_variant	Exon 7 of 14	ENST00000449726.6	NP_001183955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHA8	ENST00000449726.6	c.752A>G	p.Asp251Gly	missense_variant	Exon 7 of 14	1	NM_001197026.2	ENSP00000397947.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.752A>G (p.D251G) alteration is located in exon 7 (coding exon 7) of the PLEKHA8 gene. This alteration results from a A to G substitution at nucleotide position 752, causing the aspartic acid (D) at amino acid position 251 to be replaced by a glycine (G). 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	0.078
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T;.;.;.;T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.068	N
LIST_S2	Uncertain	0.91	D;D;D;D;D;.
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.069	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N;.;N;N;.;.
PhyloP100		2.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	N;.;N;N;N;N
REVEL	Benign	0.044
Sift	Benign	0.098	T;.;T;T;T;T
Sift4G	Benign	0.43	T;T;T;T;T;T
Polyphen		0.0	B;.;B;B;.;.
Vest4		0.093
MutPred		0.22		Loss of ubiquitination at K246 (P = 0.0416);Loss of ubiquitination at K246 (P = 0.0416);Loss of ubiquitination at K246 (P = 0.0416);Loss of ubiquitination at K246 (P = 0.0416);Loss of ubiquitination at K246 (P = 0.0416);.;
MVP		0.33
MPC		0.39
ClinPred		0.18	T
GERP RS		4.6
Varity_R		0.12
gMVP		0.24
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr7-30092438;