1-172441827-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_153747.2(PIGC):c.796C>T(p.Pro266Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.547 in 1,613,024 control chromosomes in the GnomAD database, including 249,558 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.45 (18407 hom., cov: 33)
  • Exomes 𝑓: 0.56 (231151 hom.)
• Consequence: PIGC NM_153747.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.19

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 Benign. Variant got -18 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
• BP4: Computational evidence support a benign effect (MetaRNN=1.0123705E-4).
• BP6: Variant 1-172441827-G-A is Benign according to our data. Variant chr1-172441827-G-A is described in ClinVar as [Benign]. Clinvar id is 1327021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGC	NM_153747.2	c.796C>T	p.Pro266Ser	missense_variant	2/2	ENST00000344529.5
C1orf105	NM_139240.4	c.22-3246G>A		intron_variant		ENST00000367727.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGC	ENST00000344529.5	c.796C>T	p.Pro266Ser	missense_variant	2/2	1	NM_153747.2	P1
C1orf105	ENST00000367727.9	c.22-3246G>A		intron_variant		1	NM_139240.4	P1
PIGC	ENST00000484368.1	n.96+2161C>T		intron_variant, non_coding_transcript_variant		1
PIGC	ENST00000367728.1	c.796C>T	p.Pro266Ser	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes AF: 0.452 AC: 68708 AN: 152014 Hom.: 18418 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.529

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.566

Gnomad OTH AF: 0.497

GnomAD3 exomes AF: 0.557 AC: 139685 AN: 250962 Hom.: 40646 AF XY: 0.564 AC XY: 76428 AN XY: 135622

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.619

Gnomad ASJ exome AF: 0.544

Gnomad EAS exome AF: 0.648

Gnomad SAS exome AF: 0.571

Gnomad FIN exome AF: 0.591

Gnomad NFE exome AF: 0.573

Gnomad OTH exome AF: 0.577

GnomAD4 exome AF: 0.557 AC: 814280 AN: 1460892 Hom.: 231151 Cov.: 39 AF XY: 0.560 AC XY: 406872 AN XY: 726624

Gnomad4 AFR exome AF: 0.127

Gnomad4 AMR exome AF: 0.611

Gnomad4 ASJ exome AF: 0.549

Gnomad4 EAS exome AF: 0.651

Gnomad4 SAS exome AF: 0.574

Gnomad4 FIN exome AF: 0.590

Gnomad4 NFE exome AF: 0.563

Gnomad4 OTH exome AF: 0.540

GnomAD4 genome AF: 0.452 AC: 68700 AN: 152132 Hom.: 18407 Cov.: 33 AF XY: 0.457 AC XY: 34013 AN XY: 74358

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.553

Gnomad4 ASJ AF: 0.529

Gnomad4 EAS AF: 0.648

Gnomad4 SAS AF: 0.575

Gnomad4 FIN AF: 0.581

Gnomad4 NFE AF: 0.566

Gnomad4 OTH AF: 0.491

Alfa AF: 0.551 Hom.: 51111

Bravo AF: 0.438

TwinsUK AF: 0.550 AC: 2040

ALSPAC AF: 0.563 AC: 2168

ESP6500AA AF: 0.151 AC: 665

ESP6500EA AF: 0.557 AC: 4793

ExAC AF: 0.548 AC: 66498

Asia WGS AF: 0.527 AC: 1836 AN: 3478

EpiCase AF: 0.573

EpiControl AF: 0.574

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycosylphosphatidylinositol biosynthesis defect 16 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.00010	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	2.8e-30	P;P;P;P
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.90
MPC		0.57
ClinPred		0.042	T
GERP RS		4.2
Varity_R		0.72
gMVP		0.89

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

LitVar

Other links and lift over

dbSNP: rs1063412; hg19: chr1-172410967; COSMIC: COSV51129915; COSMIC: COSV51129915;