18-62147021-T-C

Position:

• chr18-62147021-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The NM_176787.5(PIGN):​c.755A>G​(p.Asp252Gly) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D252V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIGN NM_176787.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.43

Genes affected

PIGN (HGNC:8967): (phosphatidylinositol glycan anchor biosynthesis class N) This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This protein is expressed in the endoplasmic reticulum and transfers phosphoethanolamine (EtNP) to the first mannose of the GPI anchor. Two alternatively spliced variants, which encode an identical isoform, have been reported. [provided by RefSeq, Jul 2008]

PIGN (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-62147021-T-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832
• PP5: Variant 18-62147021-T-C is Pathogenic according to our data. Variant chr18-62147021-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1012442.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGN	NM_176787.5	c.755A>G	p.Asp252Gly	missense_variant	9/31	ENST00000640252.2	NP_789744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGN	ENST00000640252.2	c.755A>G	p.Asp252Gly	missense_variant	9/31	1	NM_176787.5	ENSP00000492233.1
PIGN	ENST00000400334.7	c.755A>G	p.Asp252Gly	missense_variant	8/30	1		ENSP00000383188.2
PIGN	ENST00000638424.1	n.755A>G		non_coding_transcript_exon_variant	7/29	5		ENSP00000491963.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459886 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726292

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;T;T;T;.;.;.;.;.;T;.;.;T;.;T;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;.;.;.;.;.;D;.;D;D;.;D;D;.;D;D;D;D;.;.;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.3	M;.;M;M;M;.;.;.;.;.;M;.;.;M;.;M;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-6.5	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;D;D;D;.;.;.;.;.;D;.;.;D;.;D;.;.;.;.;.;.;.;.;.
Vest4		0.90, 0.90
MutPred		0.53		Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);.;.;Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);Gain of catalytic residue at G250 (P = 0.0583);
MVP		0.89
MPC		0.21
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs886039216; hg19: chr18-59814254;