rs17433780

chr1-89009135-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018284.3(GBP3):c.1471T>C(p.Cys491Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 1,612,222 control chromosomes in the GnomAD database, including 77,637 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C491Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.29 (6490 hom., cov: 31)
  • Exomes 𝑓: 0.31 (71147 hom.)
• Consequence: GBP3 NM_018284.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.450

Genes affected

GBP3 (HGNC:4184): (guanylate binding protein 3) This gene encodes a member of the guanylate-binding protein (GBP) family. GBPs specifically bind guanine nucleotides (GMP, GDP, and GTP) and contain two of the three consensus motifs found in typical GTP-binding proteins. The encoded protein interacts with a member of the germinal center kinase family. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002101034).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBP3	NM_018284.3	c.1471T>C	p.Cys491Arg	missense_variant	10/11	ENST00000370481.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBP3	ENST00000370481.9	c.1471T>C	p.Cys491Arg	missense_variant	10/11	1	NM_018284.3	P1

Frequencies

GnomAD3 genomes AF: 0.290 AC: 43999 AN: 151870 Hom.: 6479 Cov.: 31

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.446

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.321

GnomAD3 exomes AF: 0.281 AC: 70516 AN: 250506 Hom.: 10356 AF XY: 0.285 AC XY: 38603 AN XY: 135364

Gnomad AFR exome AF: 0.264

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.367

Gnomad EAS exome AF: 0.201

Gnomad SAS exome AF: 0.256

Gnomad FIN exome AF: 0.235

Gnomad NFE exome AF: 0.321

Gnomad OTH exome AF: 0.308

GnomAD4 exome AF: 0.309 AC: 451567 AN: 1460234 Hom.: 71147 Cov.: 34 AF XY: 0.308 AC XY: 223455 AN XY: 726438

Gnomad4 AFR exome AF: 0.269

Gnomad4 AMR exome AF: 0.232

Gnomad4 ASJ exome AF: 0.362

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.255

Gnomad4 FIN exome AF: 0.238

Gnomad4 NFE exome AF: 0.325

Gnomad4 OTH exome AF: 0.307

GnomAD4 genome AF: 0.290 AC: 44039 AN: 151988 Hom.: 6490 Cov.: 31 AF XY: 0.285 AC XY: 21187 AN XY: 74292

Gnomad4 AFR AF: 0.266

Gnomad4 AMR AF: 0.295

Gnomad4 ASJ AF: 0.356

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.250

Gnomad4 FIN AF: 0.221

Gnomad4 NFE AF: 0.317

Gnomad4 OTH AF: 0.319

Alfa AF: 0.315 Hom.: 5751

Bravo AF: 0.297

TwinsUK AF: 0.317 AC: 1177

ALSPAC AF: 0.325 AC: 1253

ESP6500AA AF: 0.255 AC: 1125

ESP6500EA AF: 0.317 AC: 2722

ExAC AF: 0.281 AC: 34158

Asia WGS AF: 0.227 AC: 792 AN: 3478

EpiCase AF: 0.322

EpiControl AF: 0.344

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.032
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	6.7
Dann	Benign	0.11
DEOGEN2	Benign	0.0080	T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.0070	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-3.1	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	4.8	N;N
REVEL	Benign	0.068
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.030
MPC		0.066
ClinPred		0.0041	T
GERP RS		1.7
Varity_R		0.082
gMVP		0.095

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

Publications

LitVar

Other links and lift over

dbSNP: rs17433780; hg19: chr1-89474818; COSMIC: COSV52518550; COSMIC: COSV52518550;