19-48837330-C-A

Variant names:

• chr19-48837330-C-A
• rs181900548
• NM_020904.3:c.2299G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020904.3(PLEKHA4):​c.2299G>T​(p.Ala767Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 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. A767P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLEKHA4 NM_020904.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.826
• Publications: 3 publications found

Genes affected

PLEKHA4 (HGNC:14339): (pleckstrin homology domain containing A4) This gene encodes a pleckstrin homology (PH) domain-containing protein. The PH domain is found near the N-terminus and contains a putative phosphatidylinositol 3, 4, 5-triphosphate-binding motif (PPBM). Elevated expression of this gene has been observed in some melanomas. Alternate splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20026213).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020904.3. 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
	PLEKHA4	NM_020904.3	MANE Select	c.2299G>T	p.Ala767Ser	missense	Exon 20 of 20	NP_065955.2	Q9H4M7-1
	PLEKHA4	NM_001438306.1		c.2311G>T	p.Ala771Ser	missense	Exon 20 of 20	NP_001425235.1
	PLEKHA4	NM_001438307.1		c.2224G>T	p.Ala742Ser	missense	Exon 19 of 19	NP_001425236.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEKHA4	ENST00000263265.11	TSL:1 MANE Select	c.2299G>T	p.Ala767Ser	missense	Exon 20 of 20	ENSP00000263265.5	Q9H4M7-1
	PLEKHA4	ENST00000355496.9	TSL:1	c.*251G>T		3_prime_UTR	Exon 17 of 17	ENSP00000347683.4	Q9H4M7-2
	PLEKHA4	ENST00000882972.1		c.2320G>T	p.Ala774Ser	missense	Exon 20 of 20	ENSP00000553031.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.83
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.55	N
REVEL	Benign	0.022
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.29	B
Vest4		0.43
MutPred		0.30		Loss of catalytic residue at A767 (P = 0.0055)
MVP		0.55
MPC		0.31
ClinPred		0.84	D
GERP RS		3.2
Varity_R		0.080
gMVP		0.046
Mutation Taster		=99/1	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: rs181900548; hg19: chr19-49340587;