14-67599842-A-T

Variant names:

• chr14-67599842-A-T
• rs2295644
• NM_004569.5:c.180+182T>A

Variant summary

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

The NM_004569.5(PIGH):​c.180+182T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 151,966 control chromosomes in the GnomAD database, including 12,487 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 0.40 (12487 hom., cov: 31)
• Consequence: PIGH NM_004569.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• Publications: 10 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.72).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004569.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGH	NM_004569.5	MANE Select	c.180+182T>A		intron	N/A	NP_004560.1	Q14442
	PIGH	NM_001440640.1		c.180+182T>A		intron	N/A	NP_001427569.1
	PIGH	NM_001440644.1		c.180+182T>A		intron	N/A	NP_001427573.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGH	ENST00000216452.9	TSL:1 MANE Select	c.180+182T>A		intron	N/A	ENSP00000216452.4	Q14442
	PIGH	ENST00000560722.5	TSL:2	c.180+182T>A		intron	N/A	ENSP00000453394.1	H0YLY9
	PIGH	ENST00000559581.5	TSL:4	c.180+182T>A		intron	N/A	ENSP00000453733.1	H0YMT4

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60795 AN: 151850 Hom.: 12487 Cov.: 31

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.550

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.382

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.400 AC: 60810 AN: 151966 Hom.: 12487 Cov.: 31 AF XY: 0.401 AC XY: 29754 AN XY: 74258

African (AFR) AF: 0.342 AC: 14188 AN: 41446

American (AMR) AF: 0.321 AC: 4903 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 1809 AN: 3466

East Asian (EAS) AF: 0.384 AC: 1983 AN: 5162

South Asian (SAS) AF: 0.430 AC: 2073 AN: 4818

European-Finnish (FIN) AF: 0.470 AC: 4954 AN: 10538

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.434 AC: 29500 AN: 67944

Other (OTH) AF: 0.383 AC: 809 AN: 2110

Alfa AF: 0.406 Hom.: 1545

Bravo AF: 0.390

Asia WGS AF: 0.391 AC: 1358 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.5
DANN	Benign	0.59
PhyloP100		1.1
PromoterAI		-0.063	Neutral
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: rs2295644; hg19: chr14-68066559; COSMIC: COSV53615395;