1-89010998-C-G

Variant names:

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

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>C​(p.Gly423Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,574 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: 𝑓 0.0000072 (0 hom., 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, 0.977

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>C	p.Gly423Ala	missense	Exon 8 of 11	NP_060754.2	Q9H0R5-1
	GBP3	NM_001436844.1		c.1187G>C	p.Gly396Ala	missense	Exon 8 of 11	NP_001423773.1	A0ABB0MVI2
	GBP3	NM_001319181.2		c.1187G>C	p.Gly396Ala	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>C	p.Gly423Ala	missense	Exon 8 of 11	ENSP00000359512.4	Q9H0R5-1
	GBP3	ENST00000493594.6	TSL:1	n.*1078G>C		non_coding_transcript_exon	Exon 9 of 12	ENSP00000456449.1	H3BRX6
	GBP3	ENST00000493594.6	TSL:1	n.*1078G>C		3_prime_UTR	Exon 9 of 12	ENSP00000456449.1	H3BRX6

Frequencies

GnomAD3 genomes AF: 0.00000721 AC: 1 AN: 138778 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000166

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000151 AC: 2 AN: 1322796 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 658636

⚠️ 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: 994854

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 AF: 0.00000721 AC: 1 AN: 138778 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 67626

African (AFR) AF: 0.00 AC: 0 AN: 40512

American (AMR) AF: 0.00 AC: 0 AN: 13428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2998

East Asian (EAS) AF: 0.00 AC: 0 AN: 4840

South Asian (SAS) AF: 0.00 AC: 0 AN: 4230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000166 AC: 1 AN: 60294

Other (OTH) AF: 0.00 AC: 0 AN: 1806

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0055	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	-5.4	D
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.96	D
Vest4		0.59
MutPred		0.89		Loss of catalytic residue at A422 (P = 0.074)
MVP		0.40
MPC		0.26
ClinPred		0.94	D
GERP RS		3.8
Varity_R		0.83
gMVP		0.19
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;