chr14-24238317-G-C

Variant names:

• chr14-24238317-G-C
• rs752218890
• NM_001002002.3:c.769G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001002002.3(GMPR2):​c.769G>C​(p.Glu257Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. E257K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GMPR2 NM_001002002.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.03
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMPR2	NM_001002002.3	c.769G>C	p.Glu257Gln	missense_variant	Exon 9 of 10	ENST00000399440.7	NP_001002002.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPR2	ENST00000399440.7	c.769G>C	p.Glu257Gln	missense_variant	Exon 9 of 10	1	NM_001002002.3	ENSP00000382369.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	.;D;D;D;.;D;D;.;.;.;.;.
Eigen	Benign	0.025
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	3.1	.;M;M;.;.;.;M;.;.;.;.;.
PhyloP100		5.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.6	.;D;D;D;.;D;D;D;N;D;D;D
REVEL	Uncertain	0.47
Sift	Benign	0.065	.;T;T;T;.;D;T;T;D;T;T;D
Sift4G	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.98, 0.97	.;D;D;.;.;.;D;D;.;.;.;.
Vest4		0.24
MutPred		0.58		Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);Gain of MoRF binding (P = 0.0334);.;.;.;Gain of MoRF binding (P = 0.0334);.;.;.;.;.;
MVP		0.85
MPC		0.39
ClinPred		0.96	D
GERP RS		3.4
PromoterAI		-0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.63
Mutation Taster		=60/40	polymorphism

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

Other links and lift over

dbSNP: rs752218890; hg19: chr14-24707523;