19-48837399-C-G

Variant names:

• chr19-48837399-C-G
• rs749466462
• NM_020904.3:c.2230G>C

Variant summary

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

The NM_020904.3(PLEKHA4):​c.2230G>C​(p.Gly744Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PLEKHA4 NM_020904.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.663
• 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: 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=0.2735806).

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.2230G>C	p.Gly744Arg	missense	Exon 20 of 20	NP_065955.2	Q9H4M7-1
	PLEKHA4	NM_001438306.1		c.2242G>C	p.Gly748Arg	missense	Exon 20 of 20	NP_001425235.1
	PLEKHA4	NM_001438307.1		c.2155G>C	p.Gly719Arg	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.2230G>C	p.Gly744Arg	missense	Exon 20 of 20	ENSP00000263265.5	Q9H4M7-1
	PLEKHA4	ENST00000355496.9	TSL:1	c.*182G>C		3_prime_UTR	Exon 17 of 17	ENSP00000347683.4	Q9H4M7-2
	PLEKHA4	ENST00000882972.1		c.2251G>C	p.Gly751Arg	missense	Exon 20 of 20	ENSP00000553031.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 247166 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

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: 0.00000684 AC: 10 AN: 1461358 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726992

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53144

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111902

Other (OTH) AF: 0.00 AC: 0 AN: 60382

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	0.18
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.66
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.13
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.18	T
Polyphen		0.99	D
Vest4		0.44
MutPred		0.40		Gain of MoRF binding (P = 0.0103)
MVP		0.43
MPC		0.61
ClinPred		0.81	D
GERP RS		2.1
Varity_R		0.068
gMVP		0.062
Mutation Taster		=94/6	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: rs749466462; hg19: chr19-49340656;