chr15-55355336-C-A

Variant names:

• chr15-55355336-C-A
• NM_004855.5:c.1569C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004855.5(PIGB):​c.1569C>A​(p.Phe523Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,458,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PIGB NM_004855.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29
• Publications: 0 publications found

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]

CCPG1 (HGNC:24227): (cell cycle progression 1) Involved in positive regulation of cell cycle and positive regulation of cell population proliferation. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

DNAAF4-CCPG1 (HGNC:43019): (DNAAF4-CCPG1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring dyslexia susceptibility 1 candidate 1 (DYX1C1) and cell cycle progression 1 (CCPG1) genes on chromosome 15. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23415005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGB	NM_004855.5	c.1569C>A	p.Phe523Leu	missense_variant	Exon 12 of 12	ENST00000164305.10	NP_004846.4
CCPG1	NM_001204450.2	c.*884G>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000442196.8	NP_001191379.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGB	ENST00000164305.10	c.1569C>A	p.Phe523Leu	missense_variant	Exon 12 of 12	1	NM_004855.5	ENSP00000164305.5
CCPG1	ENST00000442196.8	c.*884G>T		3_prime_UTR_variant	Exon 9 of 9	2	NM_001204450.2	ENSP00000403400.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1458850 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 725916

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.0000224 AC: 1 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 86122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109552

Other (OTH) AF: 0.00 AC: 0 AN: 60268

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.001453), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 523 of the PIGB protein (p.Phe523Leu). This variant is not present in population databases (gnomAD no frequency). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	Pathogenic	0.57
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0058	T;T
Eigen	Benign	0.025
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.8	L;.
PhyloP100		1.3
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.13
Sift	Uncertain	0.027	D;.
Sift4G	Benign	0.30	T;T
Polyphen		0.033	B;.
Vest4		0.040
MutPred		0.48		Loss of catalytic residue at F523 (P = 0.0221);.;
MVP		0.62
MPC		0.047
ClinPred		0.65	D
GERP RS		6.1
Varity_R		0.11
gMVP		0.49
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

hg19: chr15-55647534;