NM_153747.2:c.881G>C

Variant names:

• chr1-172441742-C-G
• rs1647325450
• NM_153747.2:c.881G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_153747.2(PIGC):​c.881G>C​(p.Arg294Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,395,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R294M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PIGC NM_153747.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.24
• Publications: 0 publications found

Genes affected

PIGC (HGNC:8960): (phosphatidylinositol glycan anchor biosynthesis class C) This gene encodes an endoplasmic reticulum associated protein that is involved in glycosylphosphatidylinositol (GPI) lipid anchor biosynthesis. The GPI lipid anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. The encoded protein is one subunit of the GPI N-acetylglucosaminyl (GlcNAc) transferase that transfers GlcNAc to phosphatidylinositol (PI) on the cytoplasmic side of the endoplasmic reticulum. Two alternatively spliced transcripts that encode the same protein have been found for this gene. A pseudogene on chromosome 11 has also been characterized. [provided by RefSeq, Jul 2008]

C1orf105 (HGNC:29591): (chromosome 1 open reading frame 105)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a chain Phosphatidylinositol N-acetylglucosaminyltransferase subunit C (size 296) in uniprot entity PIGC_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_153747.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19125468).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153747.2. 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
	PIGC	NM_153747.2	MANE Select	c.881G>C	p.Arg294Thr	missense	Exon 2 of 2	NP_714969.1	Q92535
	C1orf105	NM_139240.4	MANE Select	c.22-3331C>G		intron	N/A	NP_640333.3
	PIGC	NM_002642.4		c.881G>C	p.Arg294Thr	missense	Exon 2 of 2	NP_002633.1	Q92535

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGC	ENST00000344529.5	TSL:1 MANE Select	c.881G>C	p.Arg294Thr	missense	Exon 2 of 2	ENSP00000356701.3	Q92535
	C1orf105	ENST00000367727.9	TSL:1 MANE Select	c.22-3331C>G		intron	N/A	ENSP00000356700.4	O95561
	PIGC	ENST00000484368.1	TSL:1	n.96+2246G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1395516 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 687508

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31270

American (AMR) AF: 0.00 AC: 0 AN: 33762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21732

East Asian (EAS) AF: 0.00 AC: 0 AN: 39144

South Asian (SAS) AF: 0.0000135 AC: 1 AN: 74060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5324

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081766

Other (OTH) AF: 0.00 AC: 0 AN: 57436

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.16
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.037	D
Polyphen		0.61	P
Vest4		0.20
MutPred		0.35		Gain of glycosylation at R294 (P = 0.0349)
MVP		0.59
MPC		0.42
ClinPred		0.83	D
GERP RS		5.4
Varity_R		0.38
gMVP		0.56
Mutation Taster		=62/38	polymorphism

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: rs1647325450; hg19: chr1-172410882;