14-67600203-T-G

Variant names:

• chr14-67600203-T-G
• rs761543313
• NM_004569.5:c.1A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The ENST00000216452.9(PIGH):​c.1A>C​(p.Met1?) variant causes a initiator codon change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIGH ENST00000216452.9 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.77
• Publications: 3 publications found

Genes affected

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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 63 codons. Genomic position: 67593946. Lost 0.330 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000216452.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGH	NM_004569.5	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 4	NP_004560.1
	PIGH	NM_001440640.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 5	NP_001427569.1
	PIGH	NM_001440644.1		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 5	NP_001427573.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGH	ENST00000216452.9	TSL:1 MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 4	ENSP00000216452.4
	PIGH	ENST00000560722.5	TSL:2	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 4	ENSP00000453394.1
	PIGH	ENST00000559581.5	TSL:4	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 4	ENSP00000453733.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.033	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	-0.24	T
PhyloP100		4.8
PROVEAN	Benign	-0.47	N
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.70	P
Vest4		0.85
MutPred		0.68		Gain of loop (P = 0.4248)
MVP		0.75
ClinPred		0.99	D
GERP RS		4.7
PromoterAI		-0.38	Neutral
Varity_R		0.87
gMVP		0.54
Mutation Taster		=9/191	disease causing

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: rs761543313; hg19: chr14-68066920;