6-88891840-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003800.5(RNGTT):c.760C>G(p.Gln254Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNGTT NM_003800.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.16

Genes affected

RNGTT (HGNC:10073): (RNA guanylyltransferase and 5'-phosphatase) Enables mRNA guanylyltransferase activity and triphosphatase activity. Involved in 7-methylguanosine mRNA capping. Predicted to be located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNGTT	NM_003800.5	c.760C>G	p.Gln254Glu	missense_variant	7/16	ENST00000369485.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNGTT	ENST00000369485.9	c.760C>G	p.Gln254Glu	missense_variant	7/16	1	NM_003800.5	P1
RNGTT	ENST00000369475.7	c.760C>G	p.Gln254Glu	missense_variant	7/15	1
RNGTT	ENST00000538899.2	c.760C>G	p.Gln254Glu	missense_variant	7/12	1
RNGTT	ENST00000627296.1	n.912C>G		non_coding_transcript_exon_variant	7/14	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.760C>G (p.Q254E) alteration is located in exon 7 (coding exon 7) of the RNGTT gene. This alteration results from a C to G substitution at nucleotide position 760, causing the glutamine (Q) at amino acid position 254 to be replaced by a glutamic acid (E). 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	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.7	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.8	D;D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0030	D;D;.
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.80
MutPred		0.46		Loss of ubiquitination at K249 (P = 0.1016);Loss of ubiquitination at K249 (P = 0.1016);Loss of ubiquitination at K249 (P = 0.1016);
MVP		0.85
MPC		1.4
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.29		Position offset: -34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-89601559;