Genetic Variant GBP5:p.Arg396Gln (chr1-89263911-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_052942.5(GBP5):c.1187G>A(p.Arg396Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,611,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

GBP5
NM_052942.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0270

Variant links:

Genes affected

GBP5 (HGNC:19895): (guanylate binding protein 5) This gene belongs to the TRAFAC class dynamin-like GTPase superfamily. The encoded protein acts as an activator of NLRP3 inflammasome assembly and has a role in innate immunity and inflammation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2017]

GBP5 links:

LOC100421401 (HGNC:):

LOC100421401 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.050468475).

BP6

Variant 1-89263911-C-T is Benign according to our data. Variant chr1-89263911-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2292917.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GBP5	NM_052942.5 link	c.1187G>A	p.Arg396Gln	missense_variant	Exon 9 of 12	ENST00000370459.8	NP_443174.1
GBP5	NM_001134486.4 link	c.1187G>A	p.Arg396Gln	missense_variant	Exon 8 of 11		NP_001127958.1
GBP5	NM_001391920.1 link	c.1187G>A	p.Arg396Gln	missense_variant	Exon 9 of 10		NP_001378849.1
LOC100421401		n.89263911C>T		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBP5	ENST00000370459.8 link	c.1187G>A	p.Arg396Gln	missense_variant	Exon 9 of 12	5	NM_052942.5	ENSP00000359488.3		Q96PP8-1

Frequencies

GnomAD3 genomes

AF:

0.00000666

AC:

AN:

150112

Hom.:

Cov.:

show subpopulations

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251360

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461440

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000666

AC:

AN:

150112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73106

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

May 27, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.63

CADD

Benign

3.0

DANN

Benign

0.70

DEOGEN2

Benign

0.011

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0033

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.050

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.1

N;.

PrimateAI

Benign

0.32

PROVEAN

Benign

1.8

N;N

REVEL

Benign

0.039

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;.

Polyphen

0.0050

B;.

Vest4

0.087

MutPred

0.56

Gain of ubiquitination at K395 (P = 0.0846);Gain of ubiquitination at K395 (P = 0.0846);

MVP

0.088

ClinPred

0.026

GERP RS

0.049

Varity_R

0.030

gMVP

0.037

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over