NM_001002002.3:c.1027A>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001002002.3(GMPR2):c.1027A>G(p.Ile343Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

GMPR2
NM_001002002.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63

Publications

0 publications found

Variant links:

Genes affected

GMPR2 (HGNC:4377): (guanosine monophosphate reductase 2) This gene encodes an enzyme that catalyzes the irreversible and NADPH-dependent reductive deamination of guanosine monophosphate (GMP) to inosine monophosphate (IMP). The protein also functions in the re-utilization of free intracellular bases and purine nucleosides. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2017]

GMPR2 links:

TINF2 (HGNC:11824): (TERF1 interacting nuclear factor 2) This gene encodes one of the proteins of the shelterin, or telosome, complex which protects telomeres by allowing the cell to distinguish between telomeres and regions of DNA damage. The protein encoded by this gene is a critical part of shelterin; it interacts with the three DNA-binding proteins of the shelterin complex, and it is important for assembly of the complex. Mutations in this gene cause dyskeratosis congenita (DKC), an inherited bone marrow failure syndrome. [provided by RefSeq, Mar 2010]

TINF2 Gene-Disease associations (from GenCC):

dyskeratosis congenita, autosomal dominant 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Revesz syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Orphanet
pulmonary fibrosis
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
dyskeratosis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hoyeraal-Hreidarsson syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
thyroid gland papillary carcinoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

TINF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01977992).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMPR2	NM_001002002.3 link	c.1027A>G	p.Ile343Val	missense_variant	Exon 10 of 10	ENST00000399440.7	NP_001002002.1	Q9P2T1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPR2	ENST00000399440.7 link	c.1027A>G	p.Ile343Val	missense_variant	Exon 10 of 10	1	NM_001002002.3	ENSP00000382369.2		Q9P2T1-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000442

AC:

AN:

248788

AF XY:

0.0000370

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000445

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461284

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

726978

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.000227

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53038

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000495

AC:

AN:

1111862

Other (OTH)

AF:

0.0000331

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41448

American (AMR)

AF:

0.0000655

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000385

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000453

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000496

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1081A>G (p.I361V) alteration is located in exon 9 (coding exon 9) of the GMPR2 gene. This alteration results from a A to G substitution at nucleotide position 1081, causing the isoleucine (I) at amino acid position 361 to be replaced by a valine (V). 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

Benign

0.054

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.21

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

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.57

M_CAP

Benign

0.0035

MetaRNN

Benign

0.020

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

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.29

.;N;N;.;.;N;.;.;.;.

PhyloP100

1.6

PrimateAI

Benign

0.44

PROVEAN

Benign

0.25

.;N;N;N;.;N;N;N;N;N

REVEL

Benign

0.034

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0, 0.0010

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

Vest4

0.083

MVP

0.39

MPC

0.14

ClinPred

0.031

GERP RS

3.9

PromoterAI

0.0053

Neutral

(source)

Varity_R

0.044

gMVP

0.40

Mutation Taster

=82/18

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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NM_001002002.3:c.1027A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over