chr18-13731552-A-G

Variant names:

• chr18-13731552-A-G
• rs1014433126
• NM_003799.3:c.35A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003799.3(RNMT):​c.35A>G​(p.Lys12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,560 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RNMT NM_003799.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31
• Publications: 0 publications found

Genes affected

RNMT (HGNC:10075): (RNA guanine-7 methyltransferase) Enables RNA binding activity and mRNA (guanine-N7-)-methyltransferase activity. Involved in 7-methylguanosine mRNA capping. Located in fibrillar center and nucleoplasm. Part of mRNA cap binding activity complex; mRNA cap methyltransferase complex; and receptor complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.064983696).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003799.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNMT	NM_003799.3	MANE Select	c.35A>G	p.Lys12Arg	missense	Exon 3 of 12	NP_003790.1	O43148-1
	RNMT	NM_001308263.2		c.35A>G	p.Lys12Arg	missense	Exon 3 of 12	NP_001295192.1	O43148-2
	RNMT	NM_001378134.1		c.35A>G	p.Lys12Arg	missense	Exon 2 of 11	NP_001365063.1	O43148-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNMT	ENST00000383314.7	TSL:1 MANE Select	c.35A>G	p.Lys12Arg	missense	Exon 3 of 12	ENSP00000372804.2	O43148-1
	RNMT	ENST00000543302.6	TSL:1	c.35A>G	p.Lys12Arg	missense	Exon 2 of 11	ENSP00000446426.1	O43148-1
	RNMT	ENST00000589866.5	TSL:1	c.35A>G	p.Lys12Arg	missense	Exon 2 of 11	ENSP00000466252.1	O43148-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000423 AC: 1 AN: 236270 AF XY: 0.00000780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000334

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: 6.91e-7 AC: 1 AN: 1446560 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719092

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32276

American (AMR) AF: 0.0000249 AC: 1 AN: 40136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25390

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.00 AC: 0 AN: 83434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107180

Other (OTH) AF: 0.00 AC: 0 AN: 59722

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.012
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.16	T
Polyphen		0.0050	B
Vest4		0.22
MutPred		0.15		Loss of ubiquitination at K12 (P = 0.0017)
MVP		0.53
MPC		0.18
ClinPred		0.53	D
GERP RS		2.5
PromoterAI		0.0035	Neutral
Varity_R		0.094
gMVP		0.19
Mutation Taster		=93/7	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

Other links and lift over

dbSNP: rs1014433126; hg19: chr18-13731551;