Genetic Variant GUK1:p.Arg96Gly (chr1-228147440-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000858.7(GUK1):c.286C>G(p.Arg96Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,612,570 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R96H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GUK1
NM_000858.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.04

Variant links:

Genes affected

GUK1 (HGNC:4693): (guanylate kinase 1) The protein encoded by this gene is an enzyme that catalyzes the transfer of a phosphate group from ATP to guanosine monophosphate (GMP) to form guanosine diphosphate (GDP). The encoded protein is thought to be a good target for cancer chemotherapy. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2011]

GUK1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a mutagenesis_site Increases in kcat with GMP as substrate. (size 0) in uniprot entity KGUA_HUMAN

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUK1	NM_000858.7 link	c.286C>G	p.Arg96Gly	missense_variant	Exon 6 of 9	ENST00000312726.9	NP_000849.1	Q16774-1Q6IBG8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GUK1	ENST00000453943.6 link	c.349C>G	p.Arg117Gly	missense_variant	Exon 5 of 8	1		ENSP00000401832.2	Q16774-2B1ANH0
GUK1	ENST00000312726.9 link	n.*343C>G		non_coding_transcript_exon_variant	Exon 6 of 9	1	NM_000858.7	ENSP00000317659.5
GUK1	ENST00000312726.9 link	n.*343C>G		3_prime_UTR_variant	Exon 6 of 9	1	NM_000858.7	ENSP00000317659.5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460352

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726516

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.349C>G (p.R117G) alteration is located in exon 5 (coding exon 5) of the GUK1 gene. This alteration results from a C to G substitution at nucleotide position 349, causing the arginine (R) at amino acid position 117 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;.;T;T;.;T;T;T;T;T;T;T;T

Eigen

Benign

0.093

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.92

D;D;.;.;D;D;D;D;D;D;D;.;.

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.49

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.6

M;.;M;M;.;.;.;.;.;.;.;M;M

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-4.4

D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Benign

0.15

Sift

Uncertain

0.0020

D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.060

T;T;T;T;T;T;T;T;T;T;D;T;T

Polyphen

0.049

B;.;B;B;.;.;.;.;.;.;.;B;B

Vest4

0.47

MutPred

0.60

Gain of catalytic residue at C98 (P = 0.0649);.;Gain of catalytic residue at C98 (P = 0.0649);Gain of catalytic residue at C98 (P = 0.0649);.;.;.;Gain of catalytic residue at C98 (P = 0.0649);.;.;.;Gain of catalytic residue at C98 (P = 0.0649);Gain of catalytic residue at C98 (P = 0.0649);

MVP

0.55

MPC

0.42

ClinPred

0.98

GERP RS

5.0

Varity_R

0.66

gMVP

0.76

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