rs115958467

Variant names:

• chr17-16299976-C-A
• rs115958467
• NM_004278.4:c.424C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-16299976-C-A
• chr17-16299976-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004278.4(PIGL):​c.424C>A​(p.Leu142Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00584 in 1,611,252 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/24 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 0.0048 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (41 hom.)
• Consequence: PIGL NM_004278.4 missense, splice_region
• Scores: Splicing: ADA: 0.0009913
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 0.182
• Publications: 8 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]

PIGL Gene-Disease associations (from GenCC):

• CHIME syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet, PanelApp Australia
• syndromic intellectual disability

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hyperphosphatasia-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008395642).
• BP6: Variant 17-16299976-C-A is Benign according to our data. Variant chr17-16299976-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159705.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00481 (732/152282) while in subpopulation NFE AF = 0.00745 (507/68016). AF 95% confidence interval is 0.00692. There are 6 homozygotes in GnomAd4. There are 333 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.424C>A	p.Leu142Met	missense splice_region	Exon 3 of 7	NP_004269.1
	PIGL	NM_001411072.1		c.424C>A	p.Leu142Met	missense splice_region	Exon 3 of 6	NP_001398001.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGL	ENST00000225609.10	TSL:1 MANE Select	c.424C>A	p.Leu142Met	missense splice_region	Exon 3 of 7	ENSP00000225609.5
	PIGL	ENST00000395844.8	TSL:5	c.424C>A	p.Leu142Met	missense splice_region	Exon 3 of 6	ENSP00000379185.3
	PIGL	ENST00000584797.5	TSL:3	c.424C>A	p.Leu142Met	missense splice_region	Exon 3 of 6	ENSP00000463540.1

Frequencies

GnomAD3 genomes AF: 0.00481 AC: 732 AN: 152164 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00675

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00745

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00509 AC: 1280 AN: 251468 AF XY: 0.00520

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00535

Gnomad ASJ exome AF: 0.00804

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00768

Gnomad OTH exome AF: 0.00798

GnomAD4 exome AF: 0.00595 AC: 8681 AN: 1458970 Hom.: 41 Cov.: 28 AF XY: 0.00586 AC XY: 4255 AN XY: 726104

African (AFR) AF: 0.000987 AC: 33 AN: 33430

American (AMR) AF: 0.00575 AC: 257 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00888 AC: 232 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00133 AC: 115 AN: 86212

European-Finnish (FIN) AF: 0.00182 AC: 97 AN: 53418

Middle Eastern (MID) AF: 0.00526 AC: 30 AN: 5706

European-Non Finnish (NFE) AF: 0.00683 AC: 7581 AN: 1109402

Other (OTH) AF: 0.00558 AC: 336 AN: 60264

GnomAD4 genome AF: 0.00481 AC: 732 AN: 152282 Hom.: 6 Cov.: 32 AF XY: 0.00447 AC XY: 333 AN XY: 74448

African (AFR) AF: 0.00123 AC: 51 AN: 41566

American (AMR) AF: 0.00674 AC: 103 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00745 AC: 507 AN: 68016

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00671 Hom.: 10

Bravo AF: 0.00518

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00709 AC: 61

ExAC AF: 0.00498 AC: 604

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00774

EpiControl AF: 0.00895

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	CHIME syndrome (2)
-	1	-	Coloboma, Congenital Heart Disease, Ichthyosiform Dermatosis, Intellectual Disability, and Ear Anomalies (CHIME) Syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	0.020
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0072	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.18
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.75	N
REVEL	Uncertain	0.48
Sift	Benign	0.089	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.39
MVP		0.82
MPC		0.44
ClinPred		0.020	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.47
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00099
dbscSNV1_RF	Benign	0.014
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

Other links and lift over

dbSNP: rs115958467; hg19: chr17-16203290; COSMIC: COSV99848522;