rs1360095940

Variant names:

• chr7-30054763-A-G
• rs1360095940
• NM_001197026.2:c.851A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001197026.2(PLEKHA8):​c.851A>G​(p.Asn284Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000963 in 1,454,542 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: PLEKHA8 NM_001197026.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.218
• 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039061904).
• BP6: Variant 7-30054763-A-G is Benign according to our data. Variant chr7-30054763-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2207087.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHA8	NM_001197026.2	c.851A>G	p.Asn284Ser	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.851A>G	p.Asn284Ser	missense_variant	Exon 8 of 14	1	NM_001197026.2	ENSP00000397947.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000963 AC: 14 AN: 1454542 Hom.: 0 Cov.: 30 AF XY: 0.00000553 AC XY: 4 AN XY: 723840

African (AFR) AF: 0.00 AC: 0 AN: 33234

American (AMR) AF: 0.00 AC: 0 AN: 43728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39354

South Asian (SAS) AF: 0.00 AC: 0 AN: 85424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1107662

Other (OTH) AF: 0.00 AC: 0 AN: 60066

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 12, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.12
DANN	Benign	0.45
DEOGEN2	Benign	0.0043	T;.;.;.;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0072	N
LIST_S2	Benign	0.67	T;T;T;T;T;.
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.039	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.41	N;.;N;N;.;.
PhyloP100		0.22
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.19	N;.;N;N;N;N
REVEL	Benign	0.018
Sift	Benign	0.92	T;.;T;T;T;T
Sift4G	Benign	0.76	T;T;T;T;T;T
Polyphen		0.0	B;.;B;B;.;.
Vest4		0.041
MutPred		0.16		Gain of glycosylation at N284 (P = 0.0556);Gain of glycosylation at N284 (P = 0.0556);Gain of glycosylation at N284 (P = 0.0556);Gain of glycosylation at N284 (P = 0.0556);Gain of glycosylation at N284 (P = 0.0556);.;
MVP		0.18
MPC		0.24
ClinPred		0.025	T
GERP RS		-0.84
Varity_R		0.011
gMVP		0.10
Mutation Taster		=98/2	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: rs1360095940; hg19: chr7-30094379;