rs28668016

Variant names:

• chr15-55319235-A-G
• rs28668016
• NM_004855.5:c.-16A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004855.5(PIGB):​c.-16A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,597,260 control chromosomes in the GnomAD database, including 37,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4515 hom., cov: 32)
  • Exomes 𝑓: 0.20 (32746 hom.)
• Consequence: PIGB NM_004855.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.339
• Publications: 12 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 15-55319235-A-G is Benign according to our data. Variant chr15-55319235-A-G is described in ClinVar as [Benign]. Clinvar id is 1327019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGB	NM_004855.5	c.-16A>G		5_prime_UTR_variant	Exon 1 of 12	ENST00000164305.10	NP_004846.4
PIGBOS1	NM_001308421.2	c.-447T>C		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.-16A>G		5_prime_UTR_variant	Exon 1 of 12	1	NM_004855.5	ENSP00000164305.5
PIGBOS1	ENST00000436697.3	c.-447T>C		upstream_gene_variant		2	NM_001308421.2	ENSP00000484893.1
PIGB	ENST00000566999.5	c.-16A>G		upstream_gene_variant		3		ENSP00000456531.1

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34931 AN: 152058 Hom.: 4507 Cov.: 32

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.235

GnomAD2 exomes AF: 0.242 AC: 53676 AN: 221532 AF XY: 0.237

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.322

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.575

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.201 AC: 289767 AN: 1445084 Hom.: 32746 Cov.: 32 AF XY: 0.201 AC XY: 144396 AN XY: 717112

African (AFR) AF: 0.268 AC: 8919 AN: 33276

American (AMR) AF: 0.313 AC: 13197 AN: 42116

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4600 AN: 25494

East Asian (EAS) AF: 0.527 AC: 20626 AN: 39172

South Asian (SAS) AF: 0.274 AC: 22789 AN: 83078

European-Finnish (FIN) AF: 0.174 AC: 9107 AN: 52266

Middle Eastern (MID) AF: 0.163 AC: 931 AN: 5726

European-Non Finnish (NFE) AF: 0.178 AC: 196722 AN: 1104228

Other (OTH) AF: 0.216 AC: 12876 AN: 59728

GnomAD4 genome AF: 0.230 AC: 34960 AN: 152176 Hom.: 4515 Cov.: 32 AF XY: 0.233 AC XY: 17297 AN XY: 74390

African (AFR) AF: 0.270 AC: 11194 AN: 41488

American (AMR) AF: 0.266 AC: 4064 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 671 AN: 3470

East Asian (EAS) AF: 0.548 AC: 2837 AN: 5174

South Asian (SAS) AF: 0.290 AC: 1403 AN: 4830

European-Finnish (FIN) AF: 0.176 AC: 1862 AN: 10582

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12138 AN: 68012

Other (OTH) AF: 0.233 AC: 493 AN: 2114

Alfa AF: 0.195 Hom.: 1116

Bravo AF: 0.241

Asia WGS AF: 0.378 AC: 1315 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Developmental and epileptic encephalopathy, 80 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.4
DANN	Benign	0.63
PhyloP100		0.34
PromoterAI		-0.060	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs28668016; hg19: chr15-55611433;