7-30045120-A-G

Variant names:

• chr7-30045120-A-G
• rs941263363
• NM_001197026.2:c.76A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001197026.2(PLEKHA8):​c.76A>G​(p.Ile26Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I26M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLEKHA8 NM_001197026.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.30
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33037132).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001197026.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHA8	NM_001197026.2	MANE Select	c.76A>G	p.Ile26Val	missense	Exon 2 of 14	NP_001183955.1	A0A2P1JJM6
	PLEKHA8	NM_001197027.2		c.76A>G	p.Ile26Val	missense	Exon 2 of 14	NP_001183956.1	A0A087X1S6
	PLEKHA8	NM_001350973.2		c.76A>G	p.Ile26Val	missense	Exon 2 of 14	NP_001337902.1	Q96JA3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHA8	ENST00000449726.6	TSL:1 MANE Select	c.76A>G	p.Ile26Val	missense	Exon 2 of 14	ENSP00000397947.1	Q96JA3-1
	PLEKHA8	ENST00000440706.3	TSL:1	c.76A>G	p.Ile26Val	missense	Exon 2 of 14	ENSP00000407802.2	Q96JA3-1
	PLEKHA8	ENST00000396257.6	TSL:1	c.76A>G	p.Ile26Val	missense	Exon 2 of 14	ENSP00000379556.2	Q96JA3-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458316 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725526

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33168

American (AMR) AF: 0.00 AC: 0 AN: 44102

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.00 AC: 0 AN: 85706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110498

Other (OTH) AF: 0.00 AC: 0 AN: 60216

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.24
Eigen_PC	Benign	0.0063
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.035	N
PhyloP100		6.3
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.22
Sift	Benign	0.24	T
Sift4G	Benign	0.34	T
Polyphen		0.15	B
Vest4		0.17
MutPred		0.49		Gain of sheet (P = 0.1451)
MVP		0.78
MPC		0.28
ClinPred		0.68	D
GERP RS		5.3
Varity_R		0.10
gMVP		0.095
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs941263363; hg19: chr7-30084736;