6-88612785-A-C

Variant names:

• chr6-88612785-A-C
• rs140464652
• NM_003800.5:c.1728T>G

Variant summary

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

The NM_003800.5(RNGTT):​c.1728T>G​(p.His576Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000996 in 1,613,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H576Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: RNGTT NM_003800.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008767337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNGTT	NM_003800.5	c.1728T>G	p.His576Gln	missense_variant	Exon 16 of 16	ENST00000369485.9	NP_003791.3
RNGTT	NM_001286426.2	c.1659T>G	p.His553Gln	missense_variant	Exon 15 of 15		NP_001273355.1
RNGTT	NM_001286428.2	c.1479T>G	p.His493Gln	missense_variant	Exon 14 of 14		NP_001273357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNGTT	ENST00000369485.9	c.1728T>G	p.His576Gln	missense_variant	Exon 16 of 16	1	NM_003800.5	ENSP00000358497.4
RNGTT	ENST00000369475.7	c.1659T>G	p.His553Gln	missense_variant	Exon 15 of 15	1		ENSP00000358487.4

Frequencies

GnomAD3 genomes AF: 0.000856 AC: 130 AN: 151922 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000788

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.000700 AC: 176 AN: 251322 AF XY: 0.000707

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00101 AC: 1477 AN: 1461288 Hom.: 0 Cov.: 32 AF XY: 0.000967 AC XY: 703 AN XY: 726982

Gnomad4 AFR exome AF: 0.000179 AC: 6 AN: 33458

Gnomad4 AMR exome AF: 0.000783 AC: 35 AN: 44722

Gnomad4 ASJ exome AF: 0.000957 AC: 25 AN: 26134

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39698

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86222

Gnomad4 FIN exome AF: 0.0000936 AC: 5 AN: 53420

Gnomad4 NFE exome AF: 0.00121 AC: 1342 AN: 1111926

Gnomad4 Remaining exome AF: 0.00103 AC: 62 AN: 60360

GnomAD4 genome AF: 0.000855 AC: 130 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.000673 AC XY: 50 AN XY: 74310

Gnomad4 AFR AF: 0.000410 AC: 0.000410034 AN: 0.000410034

Gnomad4 AMR AF: 0.000787 AC: 0.000786988 AN: 0.000786988

Gnomad4 ASJ AF: 0.00115 AC: 0.00115274 AN: 0.00115274

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.0000944 AC: 0.0000944109 AN: 0.0000944109

Gnomad4 NFE AF: 0.00132 AC: 0.00132388 AN: 0.00132388

Gnomad4 OTH AF: 0.00285 AC: 0.0028463 AN: 0.0028463

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.000850

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000626 AC: 76

EpiCase AF: 0.00109

EpiControl AF: 0.00131

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1728T>G (p.H576Q) alteration is located in exon 16 (coding exon 16) of the RNGTT gene. This alteration results from a T to G substitution at nucleotide position 1728, causing the histidine (H) at amino acid position 576 to be replaced by a glutamine (Q). 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	0.086
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.0088	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.036
Sift	Benign	0.035	D;.
Sift4G	Uncertain	0.037	D;D
Polyphen		0.0020	B;B
Vest4		0.11
MutPred		0.21		Loss of catalytic residue at L578 (P = 0.0596);.;
MVP		0.28
MPC		0.59
ClinPred		0.020	T
GERP RS		3.4
Varity_R		0.061
gMVP		0.31
Mutation Taster		=61/39	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

Other links and lift over

dbSNP: rs140464652; hg19: chr6-89322504;