NM_004278.4:c.25G>T

Variant names:

• chr17-16217251-G-T
• rs1173392431
• NM_004278.4:c.25G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004278.4(PIGL):​c.25G>T​(p.Val9Leu) 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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIGL NM_004278.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.89
• Publications: 0 publications found

Genes affected

PIGL (HGNC:8966): (phosphatidylinositol glycan anchor biosynthesis class L) This gene encodes an enzyme that catalyzes the second step of glycosylphosphatidylinositol (GPI) biosynthesis, which is the de-N-acetylation of N-acetylglucosaminylphosphatidylinositol (GlcNAc-PI). Study of a similar rat enzyme suggests that this protein localizes to the endoplasmic reticulum. [provided by RefSeq, Jul 2008]

NCOR1 (HGNC:7672): (nuclear receptor corepressor 1) This gene encodes a protein that mediates ligand-independent transcription repression of thyroid-hormone and retinoic-acid receptors by promoting chromatin condensation and preventing access of the transcription machinery. It is part of a complex which also includes histone deacetylases and transcriptional regulators similar to the yeast protein Sin3p. This gene is located between the Charcot-Marie-Tooth and Smith-Magenis syndrome critical regions on chromosome 17. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 17 and 20.[provided by RefSeq, Jun 2010]

NCOR1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06498879).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004278.4. 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
	PIGL	NM_004278.4	MANE Select	c.25G>T	p.Val9Leu	missense	Exon 1 of 7	NP_004269.1	Q9Y2B2-1
	PIGL	NM_001411072.1		c.25G>T	p.Val9Leu	missense	Exon 1 of 6	NP_001398001.1	A8MTV0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGL	ENST00000225609.10	TSL:1 MANE Select	c.25G>T	p.Val9Leu	missense	Exon 1 of 7	ENSP00000225609.5	Q9Y2B2-1
	PIGL	ENST00000395844.8	TSL:5	c.25G>T	p.Val9Leu	missense	Exon 1 of 6	ENSP00000379185.3	A8MTV0
	PIGL	ENST00000584797.5	TSL:3	c.25G>T	p.Val9Leu	missense	Exon 1 of 6	ENSP00000463540.1	J3QLG8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	0.029
DANN	Benign	0.48
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.38	N
PhyloP100		-1.9
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.20
Sift	Benign	0.26	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.082
MutPred		0.42		Loss of MoRF binding (P = 0.1082)
MVP		0.40
MPC		0.17
ClinPred		0.25	T
GERP RS		-4.2
PromoterAI		-0.057	Neutral
Varity_R		0.054
gMVP		0.53
Mutation Taster		=97/3	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: rs1173392431; hg19: chr17-16120565;