NM_005482.3:c.841G>T

Variant names:

• chr1-77154594-C-A
• rs776294990
• NM_005482.3:c.841G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005482.3(PIGK):​c.841G>T​(p.Val281Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,206 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V281M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PIGK NM_005482.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47
• Publications: 0 publications found

Genes affected

PIGK (HGNC:8965): (phosphatidylinositol glycan anchor biosynthesis class K) This gene encodes a member of the cysteine protease family C13 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 a member of the multisubunit enzyme, GPI transamidase and is thought to be its enzymatic component. GPI transamidase mediates GPI anchoring in the endoplasmic reticulum, by catalyzing the transfer of fully assembled GPI units to proteins. [provided by RefSeq, Jul 2008]

PIGK Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38435405).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005482.3. 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
	PIGK	NM_005482.3	MANE Select	c.841G>T	p.Val281Leu	missense	Exon 9 of 11	NP_005473.1	Q92643-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGK	ENST00000370812.8	TSL:1 MANE Select	c.841G>T	p.Val281Leu	missense	Exon 9 of 11	ENSP00000359848.3	Q92643-1
	PIGK	ENST00000359130.1	TSL:1	c.841G>T	p.Val281Leu	missense	Exon 9 of 9	ENSP00000352041.1	A6NEM5
	PIGK	ENST00000445065.5	TSL:1	c.559G>T	p.Val187Leu	missense	Exon 6 of 8	ENSP00000388854.1	B1AK81

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460206 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726450

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110860

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Benign	0.91
DEOGEN2	Benign	0.0064	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.020
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.77	N
PhyloP100		7.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.25
Sift	Benign	0.71	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.78
MutPred		0.36		Loss of methylation at K277 (P = 0.1122)
MVP		0.18
MPC		0.14
ClinPred		0.89	D
GERP RS		5.1
Varity_R		0.22
gMVP		0.57
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs776294990; hg19: chr1-77620279;