4-533875-A-C

Variant names:

• chr4-533875-A-C
• rs758180926
• NM_001127178.3:c.2629A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001127178.3(PIGG):​c.2629A>C​(p.Thr877Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T877A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.01
• Publications: 0 publications found

Genes affected

PIGG (HGNC:25985): (phosphatidylinositol glycan anchor biosynthesis class G (EMM blood group)) This gene encodes an enzyme involved in glycosylphosphatidylinositol-anchor biosynthesis. The encoded protein, which is localized to the endoplasmic reticulum, is involved in transferring ethanoloamine phosphate to mannose 2 of glycosylphosphatidylinositol species H7 to form species H8. Allelic variants of this gene have been associated with intellectual disability, hypotonia, and early-onset seizures. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

PIGG Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 53

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19755384).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127178.3. 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
	PIGG	NM_001127178.3	MANE Select	c.2629A>C	p.Thr877Pro	missense	Exon 12 of 13	NP_001120650.1	Q5H8A4-1
	PIGG	NM_017733.5		c.2605A>C	p.Thr869Pro	missense	Exon 12 of 13	NP_060203.3
	PIGG	NM_001289051.2		c.2362A>C	p.Thr788Pro	missense	Exon 12 of 13	NP_001275980.1	E7EWV1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGG	ENST00000453061.7	TSL:1 MANE Select	c.2629A>C	p.Thr877Pro	missense	Exon 12 of 13	ENSP00000415203.2	Q5H8A4-1
	PIGG	ENST00000383028.8	TSL:1	c.2230A>C	p.Thr744Pro	missense	Exon 10 of 11	ENSP00000372494.4	Q5H8A4-3
	PIGG	ENST00000508144.1	TSL:1	n.244A>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.13
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.017	D
Polyphen		0.54	P
Vest4		0.44
MutPred		0.50		Gain of sheet (P = 0.0125)
MVP		0.29
MPC		0.27
ClinPred		0.25	T
GERP RS		-1.3
Varity_R		0.18
gMVP		0.66
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs758180926; hg19: chr4-527664;