17-16217245-C-G

Variant names:

• chr17-16217245-C-G
• rs747774912
• NM_004278.4:c.19C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_004278.4(PIGL):​c.19C>G​(p.Leu7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PIGL NM_004278.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.32

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 0 ACMG points.

• PM1: In a chain N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase (size 251) 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.06531596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGL	NM_004278.4	c.19C>G	p.Leu7Val	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.19C>G	p.Leu7Val	missense_variant	Exon 1 of 7	1	NM_004278.4	ENSP00000225609.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251344 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000254 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	0.014
DANN	Benign	0.46
DEOGEN2	Benign	0.018	T;T;T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.53	T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.065	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	.;.;L;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.64	.;.;N;N
REVEL	Benign	0.22
Sift	Benign	0.22	.;.;T;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.0010	.;.;B;.
Vest4		0.20
MutPred		0.31		Gain of catalytic residue at L7 (P = 0.0155);Gain of catalytic residue at L7 (P = 0.0155);Gain of catalytic residue at L7 (P = 0.0155);Gain of catalytic residue at L7 (P = 0.0155);
MVP		0.37
MPC		0.17
ClinPred		0.29	T
GERP RS		-9.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.61

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: rs747774912; hg19: chr17-16120559;