chr17-16217389-A-T

Variant names:

• chr17-16217389-A-T
• rs751560960
• NM_004278.4:c.163A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_004278.4(PIGL):​c.163A>T​(p.Met55Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 6.8e-7 (0 hom.)
• Consequence: PIGL NM_004278.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.30

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 3 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.3914623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGL	NM_004278.4	c.163A>T	p.Met55Leu	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.163A>T	p.Met55Leu	missense_variant	Exon 1 of 7	1	NM_004278.4	ENSP00000225609.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251490 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.0065	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Benign	0.67
DEOGEN2	Uncertain	0.56	D;D;D;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.87	D;D;T;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.7	.;.;L;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.7	.;.;D;D
REVEL	Benign	0.23
Sift	Benign	0.035	.;.;D;D
Sift4G	Benign	0.079	T;T;D;T
Polyphen		0.046	.;.;B;.
Vest4		0.43
MutPred		0.74		Loss of catalytic residue at M55 (P = 0.0413);Loss of catalytic residue at M55 (P = 0.0413);Loss of catalytic residue at M55 (P = 0.0413);Loss of catalytic residue at M55 (P = 0.0413);
MVP		0.66
MPC		0.29
ClinPred		0.95	D
GERP RS		3.2
Varity_R		0.62
gMVP		0.89

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: rs751560960; hg19: chr17-16120703;