chr1-172442043-G-T

Position:

• chr1-172442043-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_153747.2(PIGC):​c.580C>A​(p.Pro194Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIGC NM_153747.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.43

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Phosphatidylinositol N-acetylglucosaminyltransferase subunit C (size 296) in uniprot entity PIGC_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_153747.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGC	NM_153747.2	c.580C>A	p.Pro194Thr	missense_variant	2/2	ENST00000344529.5	NP_714969.1
C1orf105	NM_139240.4	c.22-3030G>T		intron_variant		ENST00000367727.9	NP_640333.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGC	ENST00000344529.5	c.580C>A	p.Pro194Thr	missense_variant	2/2	1	NM_153747.2	ENSP00000356701.3
C1orf105	ENST00000367727.9	c.22-3030G>T		intron_variant		1	NM_139240.4	ENSP00000356700.4
PIGC	ENST00000484368.1	n.96+1945C>A		intron_variant		1
PIGC	ENST00000367728.1	c.580C>A	p.Pro194Thr	missense_variant	1/1	6		ENSP00000356702.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2024

The c.580C>A (p.P194T) alteration is located in exon 2 (coding exon 1) of the PIGC gene. This alteration results from a C to A substitution at nucleotide position 580, causing the proline (P) at amino acid position 194 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	.;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.22
Sift	Benign	0.15	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.90	P;P
Vest4		0.76
MutPred		0.73		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP		0.77
MPC		0.24
ClinPred		0.91	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.69

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-172411183;