NM_004569.5:c.-51C>G

Variant names:

• chr14-67600254-G-C
• rs12587848
• NM_004569.5:c.-51C>G

Variant summary

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

The NM_004569.5(PIGH):​c.-51C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,442,662 control chromosomes in the GnomAD database, including 17,420 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 0.15 (2058 hom., cov: 34)
  • Exomes 𝑓: 0.15 (15362 hom.)
• Consequence: PIGH NM_004569.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.39
• Publications: 11 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGH	NM_004569.5	MANE Select	c.-51C>G		5_prime_UTR	Exon 1 of 4	NP_004560.1
	PIGH	NM_001440640.1		c.-51C>G		5_prime_UTR	Exon 1 of 5	NP_001427569.1
	PIGH	NM_001440644.1		c.-51C>G		5_prime_UTR	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.-51C>G		5_prime_UTR	Exon 1 of 4	ENSP00000216452.4
	PIGH	ENST00000558001.1	TSL:2	n.-51C>G		non_coding_transcript_exon	Exon 1 of 4	ENSP00000454061.1
	PIGH	ENST00000558198.5	TSL:3	n.-51C>G		non_coding_transcript_exon	Exon 1 of 3	ENSP00000452924.1

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22178 AN: 152072 Hom.: 2055 Cov.: 34

Gnomad AFR AF: 0.0728

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.157

GnomAD2 exomes AF: 0.211 AC: 15616 AN: 73944 AF XY: 0.207

Gnomad AFR exome AF: 0.0691

Gnomad AMR exome AF: 0.369

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.296

Gnomad FIN exome AF: 0.214

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.146 AC: 187791 AN: 1290474 Hom.: 15362 Cov.: 23 AF XY: 0.147 AC XY: 93298 AN XY: 632824

African (AFR) AF: 0.0662 AC: 1784 AN: 26948

American (AMR) AF: 0.348 AC: 9018 AN: 25886

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 2798 AN: 20328

East Asian (EAS) AF: 0.253 AC: 8350 AN: 33056

South Asian (SAS) AF: 0.215 AC: 14523 AN: 67432

European-Finnish (FIN) AF: 0.200 AC: 7103 AN: 35574

Middle Eastern (MID) AF: 0.153 AC: 804 AN: 5270

European-Non Finnish (NFE) AF: 0.132 AC: 134932 AN: 1022144

Other (OTH) AF: 0.157 AC: 8479 AN: 53836

GnomAD4 genome AF: 0.146 AC: 22192 AN: 152188 Hom.: 2058 Cov.: 34 AF XY: 0.152 AC XY: 11307 AN XY: 74414

African (AFR) AF: 0.0726 AC: 3018 AN: 41548

American (AMR) AF: 0.282 AC: 4318 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 436 AN: 3468

East Asian (EAS) AF: 0.299 AC: 1535 AN: 5134

South Asian (SAS) AF: 0.208 AC: 1003 AN: 4824

European-Finnish (FIN) AF: 0.206 AC: 2182 AN: 10604

Middle Eastern (MID) AF: 0.202 AC: 59 AN: 292

European-Non Finnish (NFE) AF: 0.135 AC: 9192 AN: 68006

Other (OTH) AF: 0.158 AC: 334 AN: 2110

Alfa AF: 0.0888 Hom.: 265

Bravo AF: 0.149

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.49
DANN	Benign	0.25
PhyloP100		-2.4
PromoterAI		0.037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs12587848; hg19: chr14-68066971; COSMIC: COSV107243278; COSMIC: COSV107243278;