17-16217356-C-G

Variant names:

• chr17-16217356-C-G
• rs776742163
• NM_004278.4:c.130C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004278.4(PIGL):​c.130C>G​(p.Leu44Val) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L44L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIGL NM_004278.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

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.130C>G	p.Leu44Val	missense	Exon 1 of 7	NP_004269.1	Q9Y2B2-1
	PIGL	NM_001411072.1		c.130C>G	p.Leu44Val	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.130C>G	p.Leu44Val	missense	Exon 1 of 7	ENSP00000225609.5	Q9Y2B2-1
	PIGL	ENST00000395844.8	TSL:5	c.130C>G	p.Leu44Val	missense	Exon 1 of 6	ENSP00000379185.3	A8MTV0
	PIGL	ENST00000584797.5	TSL:3	c.130C>G	p.Leu44Val	missense	Exon 1 of 6	ENSP00000463540.1	J3QLG8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	23
DANN	Benign	0.57
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.098
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.69		Loss of stability (P = 0.127)
MVP		0.89
MPC		0.56
ClinPred		0.98	D
GERP RS		4.5
PromoterAI		0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.82
Mutation Taster		=43/57	disease causing

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: rs776742163; hg19: chr17-16120670;