6-88844459-T-C

Position:

• chr6-88844459-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003800.5(RNGTT):​c.1167A>G​(p.Ile389Met) variant causes a missense change involving the alteration of a non-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: 31)
• Consequence: RNGTT NM_003800.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNGTT	NM_003800.5	c.1167A>G	p.Ile389Met	missense_variant	Exon 11 of 16	ENST00000369485.9	NP_003791.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNGTT	ENST00000369485.9	c.1167A>G	p.Ile389Met	missense_variant	Exon 11 of 16	1	NM_003800.5	ENSP00000358497.4
RNGTT	ENST00000369475.7	c.1167A>G	p.Ile389Met	missense_variant	Exon 11 of 15	1		ENSP00000358487.4
RNGTT	ENST00000538899.2	c.1167A>G	p.Ile389Met	missense_variant	Exon 11 of 12	1		ENSP00000442609.2
RNGTT	ENST00000627296.1	n.1319A>G		non_coding_transcript_exon_variant	Exon 11 of 14	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Oct 22, 2024

The c.1167A>G (p.I389M) alteration is located in exon 11 (coding exon 11) of the RNGTT gene. This alteration results from a A to G substitution at nucleotide position 1167, causing the isoleucine (I) at amino acid position 389 to be replaced by a methionine (M). 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	0.39
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	2.0	M;M;M
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	D;D;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.020	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.78
MutPred		0.67		Loss of catalytic residue at P391 (P = 0.031);Loss of catalytic residue at P391 (P = 0.031);Loss of catalytic residue at P391 (P = 0.031);
MVP		0.77
MPC		1.6
ClinPred		0.90	D
GERP RS		5.5
Varity_R		0.59
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

Other links and lift over

dbSNP: rs1419448795; hg19: chr6-89554178;