14-67587182-C-T

Position:

• chr14-67587182-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_020715.3(PLEKHH1):​c.4042C>T​(p.Arg1348*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00792 in 1,613,694 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (95 hom.)
• Consequence: PLEKHH1 NM_020715.3 stop_gained
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.294

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]

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 Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00811 (11855/1461444) while in subpopulation MID AF= 0.0248 (143/5766). AF 95% confidence interval is 0.0215. There are 95 homozygotes in gnomad4_exome. There are 5786 alleles in male gnomad4_exome subpopulation. Median coverage is 37. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEKHH1	NM_020715.3	c.4042C>T	p.Arg1348*	stop_gained	29/29	ENST00000329153.10	NP_065766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEKHH1	ENST00000329153.10	c.4042C>T	p.Arg1348*	stop_gained	29/29	1	NM_020715.3	ENSP00000330278.5

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 927 AN: 152132 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00570

Gnomad ASJ AF: 0.0423

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00844

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00769 AC: 1916 AN: 249222 Hom.: 18 AF XY: 0.00773 AC XY: 1045 AN XY: 135210

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00510

Gnomad ASJ exome AF: 0.0422

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00366

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.00952

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00811 AC: 11855 AN: 1461444 Hom.: 95 Cov.: 37 AF XY: 0.00796 AC XY: 5786 AN XY: 727012

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00530

Gnomad4 ASJ exome AF: 0.0403

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00339

Gnomad4 FIN exome AF: 0.00191

Gnomad4 NFE exome AF: 0.00849

Gnomad4 OTH exome AF: 0.00904

GnomAD4 genome AF: 0.00608 AC: 926 AN: 152250 Hom.: 10 Cov.: 32 AF XY: 0.00580 AC XY: 432 AN XY: 74448

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00569

Gnomad4 ASJ AF: 0.0423

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00844

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0102 Hom.: 19

Bravo AF: 0.00609

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00205 AC: 8

ESP6500EA AF: 0.0117 AC: 97

ExAC AF: 0.00757 AC: 915

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0115

EpiControl AF: 0.0109

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	PLEKHH1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.25	N
Vest4		0.029
ClinPred		0.094	T
GERP RS		3.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs111462449; hg19: chr14-68053899; COSMIC: COSV53615042; COSMIC: COSV53615042;