chr1-89011965-C-T

Variant names:

• chr1-89011965-C-T
• rs1188548253
• NM_018284.3:c.931G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018284.3(GBP3):​c.931G>A​(p.Glu311Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,462,354 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000072 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0000045 (1 hom.)
• Consequence: GBP3 NM_018284.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.15
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBP3	NM_018284.3	MANE Select	c.931G>A	p.Glu311Lys	missense	Exon 7 of 11	NP_060754.2	Q9H0R5-1
	GBP3	NM_001436844.1		c.931G>A	p.Glu311Lys	missense	Exon 7 of 11	NP_001423773.1	A0ABB0MVI2
	GBP3	NM_001319181.2		c.931G>A	p.Glu311Lys	missense	Exon 7 of 10	NP_001306110.1	Q9H0R5-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBP3	ENST00000370481.9	TSL:1 MANE Select	c.931G>A	p.Glu311Lys	missense	Exon 7 of 11	ENSP00000359512.4	Q9H0R5-1
	GBP3	ENST00000493594.6	TSL:1	n.*741G>A		non_coding_transcript_exon	Exon 8 of 12	ENSP00000456449.1	H3BRX6
	GBP3	ENST00000493594.6	TSL:1	n.*741G>A		3_prime_UTR	Exon 8 of 12	ENSP00000456449.1	H3BRX6

Frequencies

GnomAD3 genomes AF: 0.00000716 AC: 1 AN: 139712 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000233

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000432 AC: 1 AN: 231370 AF XY: 0.00000802

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: 0.00000454 AC: 6 AN: 1322642 Hom.: 1 Cov.: 31 AF XY: 0.00000911 AC XY: 6 AN XY: 658498

African (AFR) AF: 0.00 AC: 0 AN: 33248

American (AMR) AF: 0.00 AC: 0 AN: 42430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22708

East Asian (EAS) AF: 0.00 AC: 0 AN: 38362

South Asian (SAS) AF: 0.0000497 AC: 4 AN: 80452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 994756

Other (OTH) AF: 0.0000363 AC: 2 AN: 55106

GnomAD4 genome AF: 0.00000716 AC: 1 AN: 139712 Hom.: 0 Cov.: 26 AF XY: 0.0000147 AC XY: 1 AN XY: 68182

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40668

American (AMR) AF: 0.00 AC: 0 AN: 13662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2988

East Asian (EAS) AF: 0.00 AC: 0 AN: 4872

South Asian (SAS) AF: 0.000233 AC: 1 AN: 4296

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60554

Other (OTH) AF: 0.00 AC: 0 AN: 1830

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.037	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		4.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.24
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.54
MutPred		0.76		Gain of ubiquitination at E311 (P = 0.0211)
MVP		0.61
MPC		0.32
ClinPred		0.99	D
GERP RS		3.8
PromoterAI		0.019	Neutral
Varity_R		0.83
gMVP		0.47
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1188548253; hg19: chr1-89477648;