rs4902496

Variant names:

• chr14-67588896-C-G
• rs4902496
• ENST00000557971.5:n.5011C>G

Your query was ambiguous. Multiple possible variants found:

• chr14-67588896-C-G
• chr14-67588896-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000557971.5(PLEKHH1):​n.5011C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.73 in 152,492 control chromosomes in the GnomAD database, including 41,661 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.73 (41499 hom., cov: 31)
  • Exomes 𝑓: 0.87 (162 hom.)
• Consequence: PLEKHH1 ENST00000557971.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.526
• Publications: 6 publications found

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]

GPHN Gene-Disease associations (from GenCC):

• sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEKHH1	NM_020715.3	c.*1661C>G		3_prime_UTR_variant	Exon 29 of 29	ENST00000329153.10	NP_065766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEKHH1	ENST00000329153.10	c.*1661C>G		3_prime_UTR_variant	Exon 29 of 29	1	NM_020715.3	ENSP00000330278.5

Frequencies

GnomAD3 genomes AF: 0.729 AC: 110813 AN: 151942 Hom.: 41477 Cov.: 31

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.740

Gnomad FIN AF: 0.851

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.809

Gnomad OTH AF: 0.745

GnomAD4 exome AF: 0.873 AC: 377 AN: 432 Hom.: 162 Cov.: 0 AF XY: 0.850 AC XY: 221 AN XY: 260

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.880 AC: 373 AN: 424

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.750 AC: 3 AN: 4

GnomAD4 genome AF: 0.729 AC: 110878 AN: 152060 Hom.: 41499 Cov.: 31 AF XY: 0.732 AC XY: 54412 AN XY: 74322

African (AFR) AF: 0.552 AC: 22862 AN: 41416

American (AMR) AF: 0.808 AC: 12360 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2448 AN: 3470

East Asian (EAS) AF: 0.610 AC: 3155 AN: 5168

South Asian (SAS) AF: 0.741 AC: 3564 AN: 4808

European-Finnish (FIN) AF: 0.851 AC: 9017 AN: 10590

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.809 AC: 55035 AN: 68002

Other (OTH) AF: 0.743 AC: 1570 AN: 2112

Alfa AF: 0.729 Hom.: 2429

Bravo AF: 0.715

Asia WGS AF: 0.663 AC: 2306 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.1
DANN	Benign	0.74
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4902496; hg19: chr14-68055613;