chr17-16217250-T-G

Variant names:

• chr17-16217250-T-G
• rs528697744
• NM_004278.4:c.24T>G

Variant summary

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

The NM_004278.4(PIGL):​c.24T>G​(p.Cys8Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PIGL NM_004278.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.726
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09285697).

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.24T>G	p.Cys8Trp	missense	Exon 1 of 7	NP_004269.1	Q9Y2B2-1
	PIGL	NM_001411072.1		c.24T>G	p.Cys8Trp	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.24T>G	p.Cys8Trp	missense	Exon 1 of 7	ENSP00000225609.5	Q9Y2B2-1
	PIGL	ENST00000395844.8	TSL:5	c.24T>G	p.Cys8Trp	missense	Exon 1 of 6	ENSP00000379185.3	A8MTV0
	PIGL	ENST00000584797.5	TSL:3	c.24T>G	p.Cys8Trp	missense	Exon 1 of 6	ENSP00000463540.1	J3QLG8

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251404 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74456

African (AFR) AF: 0.0000722 AC: 3 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	0.19
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	11
DANN	Benign	0.52
DEOGEN2	Benign	0.091	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.85	L
PhyloP100		-0.73
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.26
Sift	Benign	0.11	T
Sift4G	Benign	0.090	T
Polyphen		0.0030	B
Vest4		0.33
MutPred		0.51		Gain of catalytic residue at L6 (P = 0.002)
MVP		0.29
MPC		0.17
ClinPred		0.18	T
GERP RS		-7.7
PromoterAI		-0.30	Neutral
Varity_R		0.17
gMVP		0.71
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs528697744; hg19: chr17-16120564;