1-204223481-T-C

Position:

• chr1-204223481-T-C

Variant summary

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

The NM_014935.5(PLEKHA6):​c.3136A>G​(p.Met1046Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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: 2.43

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=0.14344028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHA6	NM_014935.5	c.3136A>G	p.Met1046Val	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.3136A>G	p.Met1046Val	missense_variant	22/23	1	NM_014935.5	ENSP00000272203	P2
PLEKHA6	ENST00000637508.1	c.3508A>G	p.Met1170Val	missense_variant	26/27	5		ENSP00000490182	A2
PLEKHA6	ENST00000414478.1	c.3196A>G	p.Met1066Val	missense_variant	22/23	5		ENSP00000402046

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1388652 Hom.: 0 Cov.: 29 AF XY: 0.00000146 AC XY: 1 AN XY: 685664

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Mar 18, 2024

The c.3136A>G (p.M1046V) alteration is located in exon 22 (coding exon 20) of the PLEKHA6 gene. This alteration results from a A to G substitution at nucleotide position 3136, causing the methionine (M) at amino acid position 1046 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	0.83	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.4	N;.;N
REVEL	Benign	0.031
Sift	Uncertain	0.020	D;.;D
Sift4G	Pathogenic	0.0	D;.;T
Polyphen		0.0020	B;.;.
Vest4		0.22
MutPred		0.24		Gain of sheet (P = 0.0043);.;.;
MVP		0.068
MPC		0.11
ClinPred		0.27	T
GERP RS		0.87
Varity_R		0.10
gMVP		0.50

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: chr1-204192609;