17-16217356-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIGL NM_004278.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 229) in uniprot entity PIGL_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_004278.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGL	NM_004278.4	c.130C>G	p.Leu44Val	missense_variant	Exon 1 of 7	ENST00000225609.10	NP_004269.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGL	ENST00000225609.10	c.130C>G	p.Leu44Val	missense_variant	Exon 1 of 7	1	NM_004278.4	ENSP00000225609.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;T;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.098
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.85	T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.0	.;.;M;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.7	.;.;D;D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.59
MutPred		0.69		Loss of stability (P = 0.127);Loss of stability (P = 0.127);Loss of stability (P = 0.127);Loss of stability (P = 0.127);
MVP		0.89
MPC		0.56
ClinPred		0.98	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs776742163; hg19: chr17-16120670;