chr21-37065651-T-G

Position:

chr21-37065651-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_153682.3(PIGP):c.336A>C(p.Arg112Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00878 in 1,613,272 control chromosomes in the GnomAD database, including 811 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 137 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 674 hom. )

Consequence

PIGP
NM_153682.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.120

Variant links:

Genes affected

PIGP (HGNC:3046): (phosphatidylinositol glycan anchor biosynthesis class P) This gene encodes an enzyme involved in the first step of glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells that serves to anchor proteins to the cell surface. The encoded protein is a component of the GPI-N-acetylglucosaminyltransferase complex that catalyzes the transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI). This gene is located in the Down Syndrome critical region on chromosome 21 and is a candidate for the pathogenesis of Down syndrome. This gene has multiple pseudogenes and is a member of the phosphatidylinositol glycan anchor biosynthesis gene family. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Feb 2016]

PIGP links:

PIGP (HGNC:):

PIGP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002111882).

BP6

Variant 21-37065651-T-G is Benign according to our data. Variant chr21-37065651-T-G is described in ClinVar as [Benign]. Clinvar id is 1609322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGP	NM_153682.3 linkuse as main transcript	c.336A>C	p.Arg112Ser	missense_variant	5/5	ENST00000360525.9	NP_710149.1	P57054-2
PIGP	NM_153681.2 linkuse as main transcript	c.408A>C	p.Arg136Ser	missense_variant	4/4		NP_710148.1	P57054-1
PIGP	NM_001320480.2 linkuse as main transcript	c.336A>C	p.Arg112Ser	missense_variant	5/5		NP_001307409.1	P57054-2
PIGP	NM_016430.4 linkuse as main transcript	c.258A>C	p.Arg86Ser	missense_variant	6/6		NP_057514.2	P57054-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGP	ENST00000360525.9 linkuse as main transcript	c.336A>C	p.Arg112Ser	missense_variant	5/5	1	NM_153682.3	ENSP00000353719.3		P57054-2

Frequencies

GnomAD3 genomes

AF:

0.0161

AC:

2450

AN:

152186

Hom.:

140

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00625

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.117

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0325

Gnomad SAS

AF:

0.0348

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.0201

GnomAD3 exomes

AF:

0.0271

AC:

6734

AN:

248772

Hom.:

444

AF XY:

0.0233

AC XY:

3136

AN XY:

134666

show subpopulations

Gnomad AFR exome

AF:

0.00585

Gnomad AMR exome

AF:

0.144

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0329

Gnomad SAS exome

AF:

0.0303

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000619

Gnomad OTH exome

AF:

0.0159

GnomAD4 exome

AF:

0.00802

AC:

11710

AN:

1460968

Hom.:

674

Cov.:

AF XY:

0.00803

AC XY:

5839

AN XY:

726782

show subpopulations

Gnomad4 AFR exome

AF:

0.00616

Gnomad4 AMR exome

AF:

0.144

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0383

Gnomad4 SAS exome

AF:

0.0293

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000345

Gnomad4 OTH exome

AF:

0.0104

GnomAD4 genome

AF:

0.0161

AC:

2449

AN:

152304

Hom.:

137

Cov.:

AF XY:

0.0192

AC XY:

1427

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00633

Gnomad4 AMR

AF:

0.116

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0326

Gnomad4 SAS

AF:

0.0348

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.0199

Alfa

AF:

0.00384

Hom.:

Bravo

AF:

0.0230

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.0209

AC:

2537

Asia WGS

AF:

0.0330

AC:

114

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

PIGP-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 04, 2021

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0071

.;T;.;.;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.78

.;T;.;T;T

MetaRNN

Benign

0.0021

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

.;L;.;.;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.51

N;N;N;N;N

REVEL

Benign

0.17

Sift

Benign

0.47

T;T;T;T;T

Sift4G

Benign

0.90

T;T;T;T;T

Polyphen

0.48

.;P;.;.;.

Vest4

0.10

MutPred

0.22

.;Gain of disorder (P = 0.0815);.;.;.;

MPC

0.012

ClinPred

0.022

GERP RS

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.41

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over