6-88844398-C-T

Variant names:

• chr6-88844398-C-T
• rs772588621
• NM_003800.5:c.1228G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003800.5(RNGTT):​c.1228G>A​(p.Val410Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,613,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: RNGTT NM_003800.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.01

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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2694373).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNGTT	NM_003800.5	c.1228G>A	p.Val410Ile	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.1228G>A	p.Val410Ile	missense_variant	Exon 11 of 16	1	NM_003800.5	ENSP00000358497.4
RNGTT	ENST00000369475.7	c.1228G>A	p.Val410Ile	missense_variant	Exon 11 of 15	1		ENSP00000358487.4
RNGTT	ENST00000538899.2	c.1228G>A	p.Val410Ile	missense_variant	Exon 11 of 12	1		ENSP00000442609.2
RNGTT	ENST00000627296.1	n.1380G>A		non_coding_transcript_exon_variant	Exon 11 of 14	2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152136 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251004 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461508 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727034

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33468

Gnomad4 AMR exome AF: 0.000134 AC: 6 AN: 44682

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26130

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39682

Gnomad4 SAS exome AF: 0.0000232 AC: 2 AN: 86142

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53368

Gnomad4 NFE exome AF: 0.0000117 AC: 13 AN: 1111886

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152254 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74446

Gnomad4 AFR AF: 0.0000241 AC: 0.0000240662 AN: 0.0000240662

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000207211 AN: 0.000207211

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.0000147003 AN: 0.0000147003

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1228G>A (p.V410I) alteration is located in exon 11 (coding exon 11) of the RNGTT gene. This alteration results from a G to A substitution at nucleotide position 1228, causing the valine (V) at amino acid position 410 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	0.084
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;.
Eigen	Benign	0.050
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.5	L;L;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.51	N;N;.
REVEL	Uncertain	0.41
Sift	Benign	0.35	T;T;.
Sift4G	Benign	0.51	T;T;T
Polyphen		0.063	B;B;.
Vest4		0.30
MutPred		0.57		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.59
MPC		0.57
ClinPred		0.19	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.098
gMVP		0.23
Mutation Taster		=67/33	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: rs772588621; hg19: chr6-89554117;