6-88612788-T-A

Position:

• chr6-88612788-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003800.5(RNGTT):​c.1725A>T​(p.Lys575Asn) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RNGTT NM_003800.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.100

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0974026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNGTT	NM_003800.5	c.1725A>T	p.Lys575Asn	missense_variant	16/16	ENST00000369485.9	NP_003791.3
RNGTT	NM_001286426.2	c.1656A>T	p.Lys552Asn	missense_variant	15/15		NP_001273355.1
RNGTT	NM_001286428.2	c.1476A>T	p.Lys492Asn	missense_variant	14/14		NP_001273357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNGTT	ENST00000369485.9	c.1725A>T	p.Lys575Asn	missense_variant	16/16	1	NM_003800.5	ENSP00000358497.4
RNGTT	ENST00000369475.7	c.1656A>T	p.Lys552Asn	missense_variant	15/15	1		ENSP00000358487.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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 07, 2023

The c.1725A>T (p.K575N) alteration is located in exon 16 (coding exon 16) of the RNGTT gene. This alteration results from a A to T substitution at nucleotide position 1725, causing the lysine (K) at amino acid position 575 to be replaced by an asparagine (N). 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	0.26
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.097	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.28	N;.
REVEL	Benign	0.071
Sift	Benign	0.22	T;.
Sift4G	Benign	0.49	T;T
Polyphen		0.15	B;P
Vest4		0.16
MutPred		0.28		Loss of methylation at K575 (P = 0.0019);.;
MVP		0.47
MPC		0.83
ClinPred		0.22	T
GERP RS		2.1
Varity_R		0.089
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-89322507;