14-67562458-G-A

Position:

• chr14-67562458-G-A

Variant summary

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

The NM_020715.3(PLEKHH1):​c.827G>A​(p.Arg276Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PLEKHH1 NM_020715.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.569

Genes affected

PLEKHH1 (HGNC:17733): (pleckstrin homology, MyTH4 and FERM domain containing H1) Predicted to be located in cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

GPHN (HGNC:):

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=0.09300351).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHH1	NM_020715.3	c.827G>A	p.Arg276Lys	missense_variant	7/29	ENST00000329153.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHH1	ENST00000329153.10	c.827G>A	p.Arg276Lys	missense_variant	7/29	1	NM_020715.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461566 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727038

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

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

Mar 21, 2023

The c.827G>A (p.R276K) alteration is located in exon 7 (coding exon 6) of the PLEKHH1 gene. This alteration results from a G to A substitution at nucleotide position 827, causing the arginine (R) at amino acid position 276 to be replaced by a lysine (K). 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	0.093
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	12
DANN	Benign	0.60
DEOGEN2	Benign	0.0031	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.13
Sift	Benign	0.34	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.054
MutPred		0.36		Gain of catalytic residue at S281 (P = 0);
MVP		0.56
MPC		0.20
ClinPred		0.23	T
GERP RS		4.2
Varity_R		0.035
gMVP		0.16

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: rs2034884790; hg19: chr14-68029175;