Genetic Variant GBP3:p.Ala325Pro (chr1-89011923-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_018284.3(GBP3):c.973G>C(p.Ala325Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000756 in 1,322,732 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. A325T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

GBP3
NM_018284.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.16

Publications

0 publications found

Variant links:

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]

GBP3 links:

ENSG00000307222 (HGNC:):

ENSG00000307222 links:

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ACMG classification

Classification was made for transcript

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, 0.981

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GBP3	NM_018284.3	MANE Select	c.973G>C	p.Ala325Pro	missense	Exon 7 of 11	NP_060754.2	Q9H0R5-1
GBP3	NM_001436844.1		c.973G>C	p.Ala325Pro	missense	Exon 7 of 11	NP_001423773.1	A0ABB0MVI2
GBP3	NM_001319181.2		c.973G>C	p.Ala325Pro	missense	Exon 7 of 10	NP_001306110.1	Q9H0R5-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GBP3	ENST00000370481.9	TSL:1 MANE Select	c.973G>C	p.Ala325Pro	missense	Exon 7 of 11	ENSP00000359512.4	Q9H0R5-1
GBP3	ENST00000493594.6	TSL:1	n.*783G>C		non_coding_transcript_exon	Exon 8 of 12	ENSP00000456449.1	H3BRX6
GBP3	ENST00000493594.6	TSL:1	n.*783G>C		3_prime_UTR	Exon 8 of 12	ENSP00000456449.1	H3BRX6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.56e-7

AC:

AN:

1322732

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

658558

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33252

American (AMR)

AF:

0.00

AC:

AN:

42438

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22712

East Asian (EAS)

AF:

0.00

AC:

AN:

38370

South Asian (SAS)

AF:

0.00

AC:

AN:

80464

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5292

European-Non Finnish (NFE)

AF:

0.00000101

AC:

AN:

994822

Other (OTH)

AF:

0.00

AC:

AN:

55108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.0044

MetaRNN

Pathogenic

0.98

MetaSVM

Benign

-0.77

MutationAssessor

Pathogenic

3.9

PhyloP100

4.2

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.30

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.85

MutPred

0.92

Loss of stability (P = 0.064)

MVP

0.53

MPC

0.34

ClinPred

1.0

GERP RS

3.8

PromoterAI

-0.0018

Neutral

(source)

Varity_R

0.97

gMVP

0.74

Mutation Taster

=83/17

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over