Genetic Variant RNGTT:p.Val525Ile (chr6-88614329-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003800.5(RNGTT):c.1573G>A(p.Val525Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000868 in 1,613,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

RNGTT
NM_003800.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.84

Variant links:

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]

RNGTT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20923927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNGTT	NM_003800.5 link	c.1573G>A	p.Val525Ile	missense_variant	Exon 15 of 16	ENST00000369485.9	NP_003791.3	O60942-1Q7Z3R6
RNGTT	NM_001286426.2 link	c.1504G>A	p.Val502Ile	missense_variant	Exon 14 of 15		NP_001273355.1	O60942-2Q7Z3R6
RNGTT	NM_001286428.2 link	c.1324G>A	p.Val442Ile	missense_variant	Exon 13 of 14		NP_001273357.1	O60942Q7Z3R6B4DSJ8
RNGTT	XM_047419443.1 link	c.*63G>A		3_prime_UTR_variant	Exon 16 of 16		XP_047275399.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNGTT	ENST00000369485.9 link	c.1573G>A	p.Val525Ile	missense_variant	Exon 15 of 16	1	NM_003800.5	ENSP00000358497.4		O60942-1
RNGTT	ENST00000369475.7 link	c.1504G>A	p.Val502Ile	missense_variant	Exon 14 of 15	1		ENSP00000358487.4		O60942-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251192

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1461258

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726968

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33470

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44720

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26128

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39678

Gnomad4 SAS exome

AF:

0.000139

AC:

AN:

86224

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53402

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1111496

Gnomad4 Remaining exome

AF:

0.0000166

AC:

AN:

60374

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000207

AC:

0.000206954

AN:

0.000206954

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 31, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1573G>A (p.V525I) alteration is located in exon 15 (coding exon 15) of the RNGTT gene. This alteration results from a G to A substitution at nucleotide position 1573, causing the valine (V) at amino acid position 525 to be replaced by an isoleucine (I). 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

0.074

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.0035

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;.

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.69

N;.

REVEL

Benign

0.12

Sift

Benign

0.27

T;.

Sift4G

Benign

0.21

T;T

Polyphen

0.075

B;B

Vest4

0.40

MutPred

0.49

Loss of sheet (P = 0.0817);.;

MVP

0.32

MPC

0.63

ClinPred

0.14

GERP RS

5.3

Varity_R

0.25

gMVP

0.25

Mutation Taster

=58/42

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

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