rs114670807

chr17-16299889-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_004278.4(PIGL):c.337G>T(p.Asp113Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,611,988 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: PIGL NM_004278.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001387
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.504

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015003979).
• BP6: Variant 17-16299889-G-T is Benign according to our data. Variant chr17-16299889-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159703.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000866 (132/152344) while in subpopulation SAS AF= 0.00186 (9/4830). AF 95% confidence interval is 0.00107. There are 0 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGL	NM_004278.4	c.337G>T	p.Asp113Tyr	missense_variant, splice_region_variant	3/7	ENST00000225609.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGL	ENST00000225609.10	c.337G>T	p.Asp113Tyr	missense_variant, splice_region_variant	3/7	1	NM_004278.4	P1

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000962 AC: 242 AN: 251446 Hom.: 1 AF XY: 0.00103 AC XY: 140 AN XY: 135892

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00212

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00108 AC: 1570 AN: 1459644 Hom.: 2 Cov.: 29 AF XY: 0.00112 AC XY: 817 AN XY: 726300

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00225

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00113

Gnomad4 OTH exome AF: 0.000995

GnomAD4 genome AF: 0.000866 AC: 132 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.000832 AC XY: 62 AN XY: 74496

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000835 Hom.: 0

Bravo AF: 0.000714

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000947 AC: 115

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

CHIME syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

PIGL-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D;D;D;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.68	T;T;T;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	0.93	D;D;D;D
PrimateAI	Benign	0.35	T
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.029	.;.;B;.
Vest4		0.23
MVP		0.86
MPC		0.16
ClinPred		0.073	T
GERP RS		-0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0040
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: rs114670807; hg19: chr17-16203203;