chr7-30054720-A-G

Variant names:

• chr7-30054720-A-G
• rs1478951008
• NM_001197026.2:c.808A>G

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.808A>G​(p.Ile270Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,226 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PLEKHA8 NM_001197026.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.762
• 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=0.03878644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA8	NM_001197026.2	c.808A>G	p.Ile270Val	missense_variant	Exon 8 of 14	ENST00000449726.6	NP_001183955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHA8	ENST00000449726.6	c.808A>G	p.Ile270Val	missense_variant	Exon 8 of 14	1	NM_001197026.2	ENSP00000397947.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000416 AC: 1 AN: 240140 AF XY: 0.00000767

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1433976 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 713836

African (AFR) AF: 0.00 AC: 0 AN: 32452

American (AMR) AF: 0.00 AC: 0 AN: 41860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25684

East Asian (EAS) AF: 0.00 AC: 0 AN: 38692

South Asian (SAS) AF: 0.00 AC: 0 AN: 82832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094654

Other (OTH) AF: 0.00 AC: 0 AN: 59230

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74370

African (AFR) AF: 0.0000241 AC: 1 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.808A>G (p.I270V) alteration is located in exon 8 (coding exon 8) of the PLEKHA8 gene. This alteration results from a A to G substitution at nucleotide position 808, causing the isoleucine (I) at amino acid position 270 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	0.068
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.0
DANN	Benign	0.39
DEOGEN2	Benign	0.0068	T;.;.;.;T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.53	T;T;T;T;T;.
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.039	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	N;.;N;N;.;.
PhyloP100		0.76
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.040	N;.;N;N;N;N
REVEL	Benign	0.067
Sift	Benign	0.46	T;.;T;T;T;T
Sift4G	Benign	0.78	T;T;T;T;T;T
Polyphen		0.0	B;.;B;B;.;.
Vest4		0.14
MutPred		0.23		Loss of catalytic residue at I270 (P = 0.0278);Loss of catalytic residue at I270 (P = 0.0278);Loss of catalytic residue at I270 (P = 0.0278);Loss of catalytic residue at I270 (P = 0.0278);Loss of catalytic residue at I270 (P = 0.0278);.;
MVP		0.36
MPC		0.25
ClinPred		0.014	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.023
gMVP		0.15
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1478951008; hg19: chr7-30094336;