chr15-55319287-G-T

Variant names:

• chr15-55319287-G-T
• rs746101897
• NM_004855.5:c.37G>T

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.37G>T​(p.Gly13Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G13E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIGB NM_004855.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.989
• Publications: 3 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: Labcorp Genetics (formerly Invitae), ClinGen, 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=0.10713583).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004855.5. 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
	PIGB	NM_004855.5	MANE Select	c.37G>T	p.Gly13Trp	missense	Exon 1 of 12	NP_004846.4
	PIGBOS1	NM_001308421.2	MANE Select	c.-499C>A		upstream_gene	N/A	NP_001295350.1	A0A0B4J2F0
	RAB27A	NM_001438970.1		c.-588C>A		upstream_gene	N/A	NP_001425899.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGB	ENST00000164305.10	TSL:1 MANE Select	c.37G>T	p.Gly13Trp	missense	Exon 1 of 12	ENSP00000164305.5	Q92521
	PIGB	ENST00000566999.5	TSL:3	c.37G>T	p.Gly13Trp	missense	Exon 1 of 6	ENSP00000456531.1	H3BS45
	PIGB	ENST00000539642.5	TSL:5	c.37G>T	p.Gly13Trp	missense	Exon 1 of 12	ENSP00000438963.2	F5H1S1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1454582 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722604

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 43692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25794

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 84258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109206

Other (OTH) AF: 0.00 AC: 0 AN: 60092

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.99
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.042
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.017	D
Polyphen		0.46	P
Vest4		0.25
MutPred		0.30		Loss of disorder (P = 0.0127)
MVP		0.52
MPC		0.090
ClinPred		0.20	T
GERP RS		1.6
PromoterAI		0.025	Neutral
Varity_R		0.039
gMVP		0.26
Mutation Taster		=98/2	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

dbSNP: rs746101897; hg19: chr15-55611485;