chr7-30028800-G-C

Variant names:

• chr7-30028800-G-C
• rs1356892470
• NM_001197026.2:c.38G>C

Variant summary

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

The NM_001197026.2(PLEKHA8):​c.38G>C​(p.Ser13Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000895 in 1,117,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. S13N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: PLEKHA8 NM_001197026.2 missense, splice_region
• Scores: Splicing: ADA: 0.9198
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.56
• 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=0.39052317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA8	NM_001197026.2	c.38G>C	p.Ser13Thr	missense_variant, splice_region_variant	Exon 1 of 14	ENST00000449726.6	NP_001183955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHA8	ENST00000449726.6	c.38G>C	p.Ser13Thr	missense_variant, splice_region_variant	Exon 1 of 14	1	NM_001197026.2	ENSP00000397947.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.95e-7 AC: 1 AN: 1117818 Hom.: 0 Cov.: 30 AF XY: 0.00000188 AC XY: 1 AN XY: 530870

African (AFR) AF: 0.00 AC: 0 AN: 23584

American (AMR) AF: 0.00 AC: 0 AN: 10416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14760

East Asian (EAS) AF: 0.00 AC: 0 AN: 27660

South Asian (SAS) AF: 0.00 AC: 0 AN: 21250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4576

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 934210

Other (OTH) AF: 0.00 AC: 0 AN: 44902

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	29
DANN	Benign	0.93
DEOGEN2	Benign	0.18	T;.;.;.;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.19	T;T;T;T;T;.
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.39	T;T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.3	L;.;L;L;.;.
PhyloP100		6.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.75	N;.;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.055	T;.;T;T;T;T
Sift4G	Benign	0.31	T;T;T;T;T;T
Polyphen		1.0, 0.0010	.;.;D;B;.;.
Vest4		0.43
MutPred		0.51		.;.;.;.;.;Loss of MoRF binding (P = 0.1179);
MVP		0.85
MPC		0.30
ClinPred		0.79	D
GERP RS		5.4
PromoterAI		0.00070	Neutral
Varity_R		0.33
gMVP		0.15
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Benign	0.63
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: rs1356892470; hg19: chr7-30068416;