1-89010998-C-A

Variant names:

• chr1-89010998-C-A
• rs777766434
• NM_018284.3:c.1268G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018284.3(GBP3):​c.1268G>T​(p.Gly423Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000151 in 1,322,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G423E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: GBP3 NM_018284.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.46
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

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.1268G>T	p.Gly423Val	missense	Exon 8 of 11	NP_060754.2	Q9H0R5-1
	GBP3	NM_001436844.1		c.1187G>T	p.Gly396Val	missense	Exon 8 of 11	NP_001423773.1	A0ABB0MVI2
	GBP3	NM_001319181.2		c.1187G>T	p.Gly396Val	missense	Exon 8 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.1268G>T	p.Gly423Val	missense	Exon 8 of 11	ENSP00000359512.4	Q9H0R5-1
	GBP3	ENST00000493594.6	TSL:1	n.*1078G>T		non_coding_transcript_exon	Exon 9 of 12	ENSP00000456449.1	H3BRX6
	GBP3	ENST00000493594.6	TSL:1	n.*1078G>T		3_prime_UTR	Exon 9 of 12	ENSP00000456449.1	H3BRX6

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD2 exomes AF: 0.00000431 AC: 1 AN: 231848 AF XY: 0.00000800

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: 0.00000981

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000151 AC: 2 AN: 1322792 Hom.: 0 Cov.: 31 AF XY: 0.00000152 AC XY: 1 AN XY: 658634

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

African (AFR) AF: 0.00 AC: 0 AN: 33242

American (AMR) AF: 0.00 AC: 0 AN: 42462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22710

East Asian (EAS) AF: 0.00 AC: 0 AN: 38374

South Asian (SAS) AF: 0.00 AC: 0 AN: 80454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5308

European-Non Finnish (NFE) AF: 0.00000201 AC: 2 AN: 994850

Other (OTH) AF: 0.00 AC: 0 AN: 55102

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 26

ExAC AF: 0.00000864 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0073	T
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		5.5
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Benign	0.25
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.88		Loss of ubiquitination at K421 (P = 0.0609)
MVP		0.44
MPC		0.29
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.88
gMVP		0.39
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs777766434; hg19: chr1-89476681; COSMIC: COSV52520206; COSMIC: COSV52520206;