14-67582134-C-G

Position:

• chr14-67582134-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020715.3(PLEKHH1):​c.3350C>G​(p.Thr1117Ser) 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. 15/21 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)
• Consequence: PLEKHH1 NM_020715.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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]

PLEKHH1 (HGNC:):

PIGH (HGNC:8964): (phosphatidylinositol glycan anchor biosynthesis class H) This gene encodes an endoplasmic reticulum associated protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI anchor is a glycolipid found on many blood cells and which serves to anchor proteins to the cell surface. The protein encoded by this gene is a subunit of the GPI N-acetylglucosaminyl (GlcNAc) transferase that transfers GlcNAc to phosphatidylinositol (PI) on the cytoplasmic side of the endoplasmic reticulum. [provided by RefSeq, Jul 2008]

GPHN (HGNC:15465): (gephyrin) This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2816009).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHH1	NM_020715.3	c.3350C>G	p.Thr1117Ser	missense_variant	24/29	ENST00000329153.10	NP_065766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHH1	ENST00000329153.10	c.3350C>G	p.Thr1117Ser	missense_variant	24/29	1	NM_020715.3	ENSP00000330278.5

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 27, 2022

The c.3350C>G (p.T1117S) alteration is located in exon 24 (coding exon 23) of the PLEKHH1 gene. This alteration results from a C to G substitution at nucleotide position 3350, causing the threonine (T) at amino acid position 1117 to be replaced by a serine (S). 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	0.19
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.9	L
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.20
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.018	D
Polyphen		0.17	B
Vest4		0.43
MutPred		0.47		Gain of disorder (P = 0.0276);
MVP		0.64
MPC		0.30
ClinPred		0.86	D
GERP RS		3.9
Varity_R		0.11
gMVP		0.29

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: chr14-68048851;