15-82990056-G-C

Variant names:

• chr15-82990056-G-C
• rs200149891
• NM_031452.4:c.346G>C

Variant summary

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

The NM_031452.4(RAMAC):​c.346G>C​(p.Gly116Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000785 in 1,273,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G116S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: RAMAC NM_031452.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.78
• Publications: 0 publications found

Genes affected

RAMAC (HGNC:31022): (RNA guanine-7 methyltransferase activating subunit) Enables RNA binding activity and enzyme activator activity. Involved in methylation and recruitment of mRNA capping enzyme to RNA polymerase II holoenzyme complex. Located in nucleoplasm. Part of mRNA cap binding activity complex and mRNA cap methyltransferase complex. [provided by Alliance of Genome Resources, Apr 2022]

C15orf40 (HGNC:28443): (chromosome 15 open reading frame 40) Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000259805 (HGNC:):

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=0.3091285).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031452.4. 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
	RAMAC	NM_031452.4	MANE Select	c.346G>C	p.Gly116Arg	missense	Exon 4 of 4	NP_113640.1	Q9BTL3
	C15orf40	NM_001160116.2		c.367-899C>G		intron	N/A	NP_001153588.1	Q8WUR7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAMAC	ENST00000304191.4	TSL:1 MANE Select	c.346G>C	p.Gly116Arg	missense	Exon 4 of 4	ENSP00000307181.3	Q9BTL3
	RAMAC	ENST00000933984.1		c.370G>C	p.Gly124Arg	missense	Exon 4 of 4	ENSP00000604043.1
	RAMAC	ENST00000875578.1		c.346G>C	p.Gly116Arg	missense	Exon 5 of 5	ENSP00000545637.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 7.85e-7 AC: 1 AN: 1273306 Hom.: 0 Cov.: 18 AF XY: 0.00000159 AC XY: 1 AN XY: 629542

African (AFR) AF: 0.00 AC: 0 AN: 28462

American (AMR) AF: 0.00 AC: 0 AN: 30338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21268

East Asian (EAS) AF: 0.00 AC: 0 AN: 37822

South Asian (SAS) AF: 0.00 AC: 0 AN: 68266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5140

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 979626

Other (OTH) AF: 0.0000189 AC: 1 AN: 52866

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	-0.18	T
PhyloP100		2.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.14
MutPred		0.40		Gain of MoRF binding (P = 0.0016)
MVP		0.15
MPC		1.4
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.34
gMVP		0.26
Mutation Taster		=72/28	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: rs200149891; hg19: chr15-83658808;