19-48837369-C-T

Variant names:

• chr19-48837369-C-T
• rs374859573
• NM_020904.3:c.2260G>A

Variant summary

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

The NM_020904.3(PLEKHA4):​c.2260G>A​(p.Ala754Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,442 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. 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. A754S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PLEKHA4 NM_020904.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.929
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039915353).

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.2260G>A	p.Ala754Thr	missense	Exon 20 of 20	NP_065955.2	Q9H4M7-1
	PLEKHA4	NM_001438306.1		c.2272G>A	p.Ala758Thr	missense	Exon 20 of 20	NP_001425235.1
	PLEKHA4	NM_001438307.1		c.2185G>A	p.Ala729Thr	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.2260G>A	p.Ala754Thr	missense	Exon 20 of 20	ENSP00000263265.5	Q9H4M7-1
	PLEKHA4	ENST00000355496.9	TSL:1	c.*212G>A		3_prime_UTR	Exon 17 of 17	ENSP00000347683.4	Q9H4M7-2
	PLEKHA4	ENST00000882972.1		c.2281G>A	p.Ala761Thr	missense	Exon 20 of 20	ENSP00000553031.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461442 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727040

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.0
DANN	Benign	0.96
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.93
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.0070
Sift	Benign	0.087	T
Sift4G	Benign	0.20	T
Polyphen		0.0080	B
Vest4		0.086
MutPred		0.15		Gain of glycosylation at A754 (P = 0.0322)
MVP		0.18
MPC		0.21
ClinPred		0.078	T
GERP RS		-2.8
Varity_R		0.041
gMVP		0.046
Mutation Taster		=100/0	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: rs374859573; hg19: chr19-49340626;