chr1-204223501-C-T

Position:

• chr1-204223501-C-T

Variant summary

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

The NM_014935.5(PLEKHA6):​c.3116G>A​(p.Gly1039Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PLEKHA6 NM_014935.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.396

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=0.2008188).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHA6	NM_014935.5	c.3116G>A	p.Gly1039Asp	missense_variant	22/23	ENST00000272203.8	NP_055750.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHA6	ENST00000272203.8	c.3116G>A	p.Gly1039Asp	missense_variant	22/23	1	NM_014935.5	ENSP00000272203	P2
PLEKHA6	ENST00000637508.1	c.3488G>A	p.Gly1163Asp	missense_variant	26/27	5		ENSP00000490182	A2
PLEKHA6	ENST00000414478.1	c.3176G>A	p.Gly1059Asp	missense_variant	22/23	5		ENSP00000402046

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398006 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 689664

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.28e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Sep 27, 2021

The c.3116G>A (p.G1039D) alteration is located in exon 22 (coding exon 20) of the PLEKHA6 gene. This alteration results from a G to A substitution at nucleotide position 3116, causing the glycine (G) at amino acid position 1039 to be replaced by an aspartic acid (D). 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	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T;T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.;.
MutationTaster	Benign	0.73	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.92	N;.;N
REVEL	Benign	0.10
Sift	Uncertain	0.014	D;.;D
Sift4G	Benign	0.21	T;.;T
Polyphen		1.0	D;.;.
Vest4		0.22
MutPred		0.13		Loss of MoRF binding (P = 0.0197);.;.;
MVP		0.10
MPC		0.14
ClinPred		0.70	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.27

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: rs1282276889; hg19: chr1-204192629;