chr1-172441964-A-G

Position:

chr1-172441964-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_153747.2(PIGC):c.659T>C(p.Leu220Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PIGC
NM_153747.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 8.54

Variant links:

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]

PIGC links:

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

C1orf105 links:

PIGC (HGNC:):

PIGC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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, 0.874

PP5

Variant 1-172441964-A-G is Pathogenic according to our data. Variant chr1-172441964-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190451.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGC	NM_153747.2 linkuse as main transcript	c.659T>C	p.Leu220Pro	missense_variant	2/2	ENST00000344529.5	NP_714969.1	Q92535
C1orf105	NM_139240.4 linkuse as main transcript	c.22-3109A>G		intron_variant		ENST00000367727.9	NP_640333.3	O95561

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PIGC	ENST00000344529.5 linkuse as main transcript	c.659T>C	p.Leu220Pro	missense_variant	2/2	1	NM_153747.2	ENSP00000356701.3	Q92535
C1orf105	ENST00000367727.9 linkuse as main transcript	c.22-3109A>G		intron_variant		1	NM_139240.4	ENSP00000356700.4	O95561
PIGC	ENST00000484368.1 linkuse as main transcript	n.96+2024T>C		intron_variant		1
PIGC	ENST00000367728.1 linkuse as main transcript	c.659T>C	p.Leu220Pro	missense_variant	1/1	6		ENSP00000356702.1	Q92535

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Non-immune hydrops fetalis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 22, 2014

- -

Glycosylphosphatidylinositol biosynthesis defect 16

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

T;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.81

.;T

M_CAP

Benign

0.057

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.0

M;M

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.1

D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;D

Vest4

0.92

MutPred

0.72

Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);

MVP

0.73

MPC

0.74

ClinPred

0.99

GERP RS

5.5

Varity_R

0.98

gMVP

0.96

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over