chr17-16299906-A-G

Position:

• chr17-16299906-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_004278.4(PIGL):​c.354A>G​(p.Pro118Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,613,726 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (5 hom.)
• Consequence: PIGL NM_004278.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: -0.403

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]

PIGL (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-16299906-A-G is Benign according to our data. Variant chr17-16299906-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159704.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BP7: Synonymous conserved (PhyloP=-0.403 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000169 (247/1461372) while in subpopulation MID AF= 0.0101 (58/5760). AF 95% confidence interval is 0.008. There are 5 homozygotes in gnomad4_exome. There are 125 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGL	NM_004278.4	c.354A>G	p.Pro118Pro	synonymous_variant	3/7	ENST00000225609.10	NP_004269.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGL	ENST00000225609.10	c.354A>G	p.Pro118Pro	synonymous_variant	3/7	1	NM_004278.4	ENSP00000225609.5

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000143 AC: 36 AN: 251466 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135908

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000169 AC: 247 AN: 1461372 Hom.: 5 Cov.: 29 AF XY: 0.000172 AC XY: 125 AN XY: 727022

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.0000939 AC XY: 7 AN XY: 74514

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.000110

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 03, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	PIGL: BP4, BP7 -

CHIME syndrome Uncertain:2

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 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.9
DANN	Benign	0.81

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: rs149094276; hg19: chr17-16203220;