chr1-89009135-A-G

Variant names:

• chr1-89009135-A-G
• rs17433780
• NM_018284.3:c.1471T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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. 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
• Publications: 49 publications found

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]

ENSG00000307222 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018284.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBP3	NM_018284.3	MANE Select	c.1471T>C	p.Cys491Arg	missense	Exon 10 of 11	NP_060754.2
	GBP3	NM_001436844.1		c.1390T>C	p.Cys464Arg	missense	Exon 10 of 11	NP_001423773.1
	GBP3	NM_001319181.2		c.1390T>C	p.Cys464Arg	missense	Exon 10 of 10	NP_001306110.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBP3	ENST00000370481.9	TSL:1 MANE Select	c.1471T>C	p.Cys491Arg	missense	Exon 10 of 11	ENSP00000359512.4
	GBP3	ENST00000489444.6	TSL:1	n.*104T>C		non_coding_transcript_exon	Exon 8 of 9	ENSP00000437168.2
	GBP3	ENST00000493594.6	TSL:1	n.*1281T>C		non_coding_transcript_exon	Exon 11 of 12	ENSP00000456449.1

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

GnomAD2 exomes AF: 0.281 AC: 70516 AN: 250506 AF XY: 0.285

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 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

African (AFR) AF: 0.269 AC: 9007 AN: 33422

American (AMR) AF: 0.232 AC: 10365 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 9467 AN: 26124

East Asian (EAS) AF: 0.184 AC: 7298 AN: 39684

South Asian (SAS) AF: 0.255 AC: 21972 AN: 86218

European-Finnish (FIN) AF: 0.238 AC: 12712 AN: 53322

Middle Eastern (MID) AF: 0.281 AC: 1617 AN: 5762

European-Non Finnish (NFE) AF: 0.325 AC: 360585 AN: 1110716

Other (OTH) AF: 0.307 AC: 18544 AN: 60330

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

African (AFR) AF: 0.266 AC: 11025 AN: 41438

American (AMR) AF: 0.295 AC: 4503 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1235 AN: 3470

East Asian (EAS) AF: 0.203 AC: 1046 AN: 5158

South Asian (SAS) AF: 0.250 AC: 1201 AN: 4812

European-Finnish (FIN) AF: 0.221 AC: 2324 AN: 10538

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21551 AN: 67980

Other (OTH) AF: 0.319 AC: 673 AN: 2108

Alfa AF: 0.316 Hom.: 16683

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 v4.9

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
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-3.1	N
PhyloP100		0.45
PrimateAI	Benign	0.25	T
PROVEAN	Benign	4.8	N
REVEL	Benign	0.068
Sift	Benign	1.0	T
Sift4G	Benign	1.0	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
Mutation Taster		=100/0	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: rs17433780; hg19: chr1-89474818; COSMIC: COSV52518550; COSMIC: COSV52518550;