chr15-55319260-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004855.5(PIGB):c.10C>T(p.Pro4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000878 in 1,606,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

PIGB
NM_004855.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.719

Variant links:

Genes affected

PIGB (HGNC:8959): (phosphatidylinositol glycan anchor biosynthesis class B) This gene encodes a transmembrane protein that is located in the endoplasmic reticulum and is involved in GPI-anchor biosynthesis. The glycosylphosphatidylinositol (GPI) anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This gene is thought to encode a member of a family of dolichol-phosphate-mannose (Dol-P-Man) dependent mannosyltransferases. [provided by RefSeq, Jul 2008]

PIGB links:

PIGBOS1 (HGNC:50696): (PIGB opposite strand 1) Involved in regulation of endoplasmic reticulum unfolded protein response. Is integral component of mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

PIGBOS1 links:

RAB27A (HGNC:9766): (RAB27A, member RAS oncogene family) The protein encoded by this gene belongs to the small GTPase superfamily, Rab family. The protein is membrane-bound and may be involved in protein transport and small GTPase mediated signal transduction. Mutations in this gene are associated with Griscelli syndrome type 2. Alternative splicing occurs at this locus and four transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

RAB27A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.059782237).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGB	NM_004855.5 link	c.10C>T	p.Pro4Ser	missense_variant	Exon 1 of 12	ENST00000164305.10	NP_004846.4	Q92521
PIGBOS1	NM_001308421.2 link	c.-472G>A		upstream_gene_variant		ENST00000436697.3	NP_001295350.1	A0A0B4J2F0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PIGB	ENST00000164305.10 link	c.10C>T	p.Pro4Ser	missense_variant	Exon 1 of 12	1	NM_004855.5	ENSP00000164305.5	Q92521
PIGB	ENST00000566999.5 link	c.10C>T	p.Pro4Ser	missense_variant	Exon 1 of 6	3		ENSP00000456531.1	H3BS45
PIGBOS1	ENST00000436697.3 link	c.-472G>A		upstream_gene_variant		2	NM_001308421.2	ENSP00000484893.1	A0A0B4J2F0

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000342

AC:

AN:

233716

Hom.:

AF XY:

0.0000315

AC XY:

AN XY:

127012

show subpopulations

Gnomad AFR exome

AF:

0.0000744

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000579

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000566

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000922

AC:

134

AN:

1453872

Hom.:

Cov.:

AF XY:

0.0000955

AC XY:

AN XY:

722168

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000115

Gnomad4 OTH exome

AF:

0.0000500

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000680

ExAC

AF:

0.0000497

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10C>T (p.P4S) alteration is located in exon 1 (coding exon 1) of the PIGB gene. This alteration results from a C to T substitution at nucleotide position 10, causing the proline (P) at amino acid position 4 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

May 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 4 of the PIGB protein (p.Pro4Ser). This variant is present in population databases (rs765931863, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with PIGB-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.81

DANN

Benign

0.89

DEOGEN2

Benign

0.0018

T;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0095

LIST_S2

Benign

0.51

T;T;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.060

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.;.

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.47

N;N;.

REVEL

Benign

0.027

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.047

B;.;.

Vest4

0.090

MutPred

0.19

Gain of phosphorylation at P4 (P = 0.0101);Gain of phosphorylation at P4 (P = 0.0101);Gain of phosphorylation at P4 (P = 0.0101);

MVP

0.20

MPC

0.10

ClinPred

0.60

GERP RS

-4.8

Varity_R

0.064

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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