chr1-204228762-C-A

Position:

• chr1-204228762-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014935.5(PLEKHA6):​c.2851G>T​(p.Val951Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLEKHA6 NM_014935.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.41

Genes affected

PLEKHA6 (HGNC:17053): (pleckstrin homology domain containing A6)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22607991).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHA6	NM_014935.5	c.2851G>T	p.Val951Leu	missense_variant	20/23	ENST00000272203.8	NP_055750.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHA6	ENST00000272203.8	c.2851G>T	p.Val951Leu	missense_variant	20/23	1	NM_014935.5	ENSP00000272203	P2
PLEKHA6	ENST00000637508.1	c.3223G>T	p.Val1075Leu	missense_variant	24/27	5		ENSP00000490182	A2
PLEKHA6	ENST00000414478.1	c.2911G>T	p.Val971Leu	missense_variant	20/23	5		ENSP00000402046

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2024

The c.2851G>T (p.V951L) alteration is located in exon 20 (coding exon 18) of the PLEKHA6 gene. This alteration results from a G to T substitution at nucleotide position 2851, causing the valine (V) at amino acid position 951 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.065	T;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L;.;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.3	N;.;N
REVEL	Benign	0.14
Sift	Benign	0.21	T;.;T
Sift4G	Benign	0.15	T;.;T
Polyphen		0.93	P;.;.
Vest4		0.19
MutPred		0.15		Loss of methylation at K950 (P = 0.0359);.;.;
MVP		0.10
MPC		0.12
ClinPred		0.49	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs1201343517; hg19: chr1-204197890;