1-204228118-G-T

Position:

• chr1-204228118-G-T

Variant summary

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

The NM_014935.5(PLEKHA6):​c.2996C>A​(p.Ala999Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 9.23

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHA6	NM_014935.5	c.2996C>A	p.Ala999Glu	missense_variant	21/23	ENST00000272203.8	NP_055750.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHA6	ENST00000272203.8	c.2996C>A	p.Ala999Glu	missense_variant	21/23	1	NM_014935.5	ENSP00000272203.2
PLEKHA6	ENST00000637508.1	c.3368C>A	p.Ala1123Glu	missense_variant	25/27	5		ENSP00000490182.1
PLEKHA6	ENST00000414478.1	c.3056C>A	p.Ala1019Glu	missense_variant	21/23	5		ENSP00000402046.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Dec 03, 2024

The c.2996C>A (p.A999E) alteration is located in exon 21 (coding exon 19) of the PLEKHA6 gene. This alteration results from a C to A substitution at nucleotide position 2996, causing the alanine (A) at amino acid position 999 to be replaced by a glutamic acid (E). 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	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.7	M;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0030	D;.;D
Sift4G	Uncertain	0.012	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.97
MutPred		0.27		Loss of MoRF binding (P = 0.0256);.;.;
MVP		0.37
MPC		0.49
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.80
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-204197246;