NM_004855.5:c.8G>C

Variant names:

• chr15-55319258-G-C
• rs772860275
• NM_004855.5:c.8G>C

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.8G>C​(p.Arg3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PIGB NM_004855.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70
• 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]

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]

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 Gene-Disease associations (from GenCC):

• Griscelli syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

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=0.08243024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGB	NM_004855.5	c.8G>C	p.Arg3Thr	missense_variant	Exon 1 of 12	ENST00000164305.10	NP_004846.4
PIGBOS1	NM_001308421.2	c.-470C>G		upstream_gene_variant		ENST00000436697.3	NP_001295350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGB	ENST00000164305.10	c.8G>C	p.Arg3Thr	missense_variant	Exon 1 of 12	1	NM_004855.5	ENSP00000164305.5
PIGB	ENST00000566999.5	c.8G>C	p.Arg3Thr	missense_variant	Exon 1 of 6	3		ENSP00000456531.1
PIGBOS1	ENST00000436697.3	c.-470C>G		upstream_gene_variant		2	NM_001308421.2	ENSP00000484893.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000129 AC: 3 AN: 233380 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453710 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722094

⚠️ 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: 33362

American (AMR) AF: 0.00 AC: 0 AN: 43564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25766

East Asian (EAS) AF: 0.00 AC: 0 AN: 39500

South Asian (SAS) AF: 0.0000357 AC: 3 AN: 84064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108886

Other (OTH) AF: 0.00 AC: 0 AN: 60038

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.008463), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000829 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	8.3
DANN	Benign	0.41
DEOGEN2	Benign	0.0020	T;T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.48	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.082	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N;.;.
PhyloP100		1.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.050	N;N;.
REVEL	Benign	0.050
Sift	Pathogenic	0.0	D;D;.
Sift4G	Benign	0.68	T;T;T
Polyphen		0.039	B;.;.
Vest4		0.17
MutPred		0.21		Loss of MoRF binding (P = 0.0033);Loss of MoRF binding (P = 0.0033);Loss of MoRF binding (P = 0.0033);
MVP		0.46
MPC		0.055
ClinPred		0.31	T
GERP RS		2.8
PromoterAI		-0.085	Neutral
Varity_R		0.11
gMVP		0.51

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

dbSNP: rs772860275; hg19: chr15-55611456;