1-89056855-G-C

Variant names:

• chr1-89056855-G-C
• rs147875713
• NM_002053.3:c.1154C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002053.3(GBP1):​c.1154C>G​(p.Ala385Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. A385V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GBP1 NM_002053.3 missense, splice_region
• Scores: Splicing: ADA: 0.001084
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.32
• Publications: 0 publications found

Genes affected

GBP1 (HGNC:4182): (guanylate binding protein 1) Guanylate binding protein expression is induced by interferon. Guanylate binding proteins are characterized by their ability to specifically bind guanine nucleotides (GMP, GDP, and GTP) and are distinguished from the GTP-binding proteins by the presence of 2 binding motifs rather than 3. [provided by RefSeq, Jul 2008]

ENSG00000307222 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042684853).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002053.3. 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
	GBP1	NM_002053.3	MANE Select	c.1154C>G	p.Ala385Gly	missense splice_region	Exon 7 of 11	NP_002044.2	P32455

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBP1	ENST00000370473.5	TSL:1 MANE Select	c.1154C>G	p.Ala385Gly	missense splice_region	Exon 7 of 11	ENSP00000359504.4	P32455
	GBP1	ENST00000872735.1		c.1154C>G	p.Ala385Gly	missense splice_region	Exon 7 of 11	ENSP00000542794.1
	GBP1	ENST00000872736.1		c.1154C>G	p.Ala385Gly	missense splice_region	Exon 7 of 11	ENSP00000542795.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461376 Hom.: 0 Cov.: 45 AF XY: 0.00 AC XY: 0 AN XY: 726946

⚠️ 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: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111618

Other (OTH) AF: 0.00 AC: 0 AN: 60366

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.072
DANN	Benign	0.22
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.039	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.14	N
PhyloP100		-6.3
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.012
Sift	Benign	0.49	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.44		Loss of ubiquitination at K382 (P = 0.1202)
MVP		0.15
MPC		0.075
ClinPred		0.025	T
GERP RS		-9.6
Varity_R		0.16
gMVP		0.083
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.054
SpliceAI score (max)		0.14		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: rs147875713; hg19: chr1-89522538;