7-30052818-A-T

Variant names:

• chr7-30052818-A-T
• rs1792531635
• NM_001197026.2:c.748A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001197026.2(PLEKHA8):​c.748A>T​(p.Ile250Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I250V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PLEKHA8 NM_001197026.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052608967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA8	NM_001197026.2	c.748A>T	p.Ile250Leu	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.748A>T	p.Ile250Leu	missense_variant	Exon 7 of 14	1	NM_001197026.2	ENSP00000397947.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424092 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 708266

African (AFR) AF: 0.00 AC: 0 AN: 30632

American (AMR) AF: 0.00 AC: 0 AN: 32536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24678

East Asian (EAS) AF: 0.00 AC: 0 AN: 38850

South Asian (SAS) AF: 0.00 AC: 0 AN: 79170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100588

Other (OTH) AF: 0.00 AC: 0 AN: 58878

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.014	T;.;.;.;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.81	T;T;T;T;T;.
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.053	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;N;N;.;.
PhyloP100		1.2
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.17	N;.;N;N;N;N
REVEL	Benign	0.038
Sift	Benign	0.34	T;.;T;T;T;T
Sift4G	Benign	0.69	T;T;T;T;T;T
Polyphen		0.0	B;.;B;B;.;.
Vest4		0.15
MutPred		0.25		Loss of catalytic residue at I250 (P = 0.0937);Loss of catalytic residue at I250 (P = 0.0937);Loss of catalytic residue at I250 (P = 0.0937);Loss of catalytic residue at I250 (P = 0.0937);Loss of catalytic residue at I250 (P = 0.0937);.;
MVP		0.40
MPC		0.30
ClinPred		0.083	T
GERP RS		4.8
Varity_R		0.076
gMVP		0.11
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

dbSNP: rs1792531635; hg19: chr7-30092434;