rs761543313

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr14-67600203-T-A
• chr14-67600203-T-C
• chr14-67600203-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Moderate PP5

The ENST00000216452.9(PIGH):​c.1A>T​(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.0000127 in 1,420,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PIGH ENST00000216452.9 initiator_codon
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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 3 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.
• PP5: Variant 14-67600203-T-A is Pathogenic according to our data. Variant chr14-67600203-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 545630.Status of the report is no_assertion_criteria_provided, 0 stars.

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>T	p.Met1?	initiator_codon	Exon 1 of 4	NP_004560.1
	PIGH	NM_001440640.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 5	NP_001427569.1
	PIGH	NM_001440644.1		c.1A>T	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>T	p.Met1?	initiator_codon	Exon 1 of 4	ENSP00000216452.4
	PIGH	ENST00000560722.5	TSL:2	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 4	ENSP00000453394.1
	PIGH	ENST00000559581.5	TSL:4	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 4	ENSP00000453733.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000225 AC: 4 AN: 177418 AF XY: 0.0000309

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000127 AC: 18 AN: 1420360 Hom.: 0 Cov.: 32 AF XY: 0.0000199 AC XY: 14 AN XY: 703600

African (AFR) AF: 0.00 AC: 0 AN: 32264

American (AMR) AF: 0.00 AC: 0 AN: 40152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25378

East Asian (EAS) AF: 0.00 AC: 0 AN: 37324

South Asian (SAS) AF: 0.000220 AC: 18 AN: 81784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092190

Other (OTH) AF: 0.00 AC: 0 AN: 58790

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000257 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Glycosylphosphatidylinositol biosynthesis defect 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.055	T
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	0.69	D
MetaRNN	Pathogenic	0.84	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		0.98	D
GERP RS		4.7
PromoterAI		-0.32	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.87
gMVP		0.54
Mutation Taster		=9/191	disease causing (ClinVar)

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;