rs373359143

Variant names:

• chr19-48839233-A-G
• rs373359143
• NM_020904.3:c.1936T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020904.3(PLEKHA4):​c.1936T>C​(p.Trp646Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 1,596,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PLEKHA4 NM_020904.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041860193).

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.1936T>C	p.Trp646Arg	missense	Exon 18 of 20	NP_065955.2	Q9H4M7-1
	PLEKHA4	NM_001438306.1		c.1948T>C	p.Trp650Arg	missense	Exon 18 of 20	NP_001425235.1
	PLEKHA4	NM_001438307.1		c.1861T>C	p.Trp621Arg	missense	Exon 17 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.1936T>C	p.Trp646Arg	missense	Exon 18 of 20	ENSP00000263265.5	Q9H4M7-1
	PLEKHA4	ENST00000355496.9	TSL:1	c.1669-1104T>C		intron	N/A	ENSP00000347683.4	Q9H4M7-2
	PLEKHA4	ENST00000882972.1		c.1957T>C	p.Trp653Arg	missense	Exon 18 of 20	ENSP00000553031.1

Frequencies

GnomAD3 genomes AF: 0.0000922 AC: 14 AN: 151816 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

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: 0.000479

GnomAD2 exomes AF: 0.0000444 AC: 11 AN: 247938 AF XY: 0.0000372

Gnomad AFR exome AF: 0.000684

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 20 AN: 1444168 Hom.: 0 Cov.: 30 AF XY: 0.00000974 AC XY: 7 AN XY: 718470

African (AFR) AF: 0.000543 AC: 18 AN: 33160

American (AMR) AF: 0.0000229 AC: 1 AN: 43638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25674

East Asian (EAS) AF: 0.00 AC: 0 AN: 39296

South Asian (SAS) AF: 0.00 AC: 0 AN: 84246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100404

Other (OTH) AF: 0.0000169 AC: 1 AN: 59298

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 151934 Hom.: 0 Cov.: 31 AF XY: 0.0000943 AC XY: 7 AN XY: 74248

African (AFR) AF: 0.000290 AC: 12 AN: 41428

American (AMR) AF: 0.0000657 AC: 1 AN: 15214

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67982

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000219 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

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	Pathogenic	0.65
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.0064	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.57	N
REVEL	Benign	0.035
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.16	T
Polyphen		0.23	B
Vest4		0.31
MutPred		0.39		Gain of methylation at W646 (P = 0.0119)
MVP		0.38
MPC		0.60
ClinPred		0.15	T
GERP RS		2.7
Varity_R		0.12
gMVP		0.12
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs373359143; hg19: chr19-49342490;