Genetic Variant NM_031452.4:c.346G>A (chr15-82990056-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_031452.4(RAMAC):c.346G>A(p.Gly116Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,406,700 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 0.00020 ( 0 hom., cov: 26)

Exomes 𝑓: 0.00042 ( 0 hom. )

Consequence

RAMAC
NM_031452.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.78

Publications

0 publications found

Variant links:

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]

RAMAC links:

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

C15orf40 links:

ENSG00000259805 (HGNC:):

ENSG00000259805 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.1970855).

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>A	p.Gly116Ser	missense	Exon 4 of 4	NP_113640.1	Q9BTL3
	C15orf40	NM_001160116.2		c.367-899C>T		intron	N/A	NP_001153588.1	Q8WUR7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAMAC	ENST00000304191.4	TSL:1 MANE Select	c.346G>A	p.Gly116Ser	missense	Exon 4 of 4	ENSP00000307181.3	Q9BTL3
RAMAC	ENST00000933984.1		c.370G>A	p.Gly124Ser	missense	Exon 4 of 4	ENSP00000604043.1
RAMAC	ENST00000875578.1		c.346G>A	p.Gly116Ser	missense	Exon 5 of 5	ENSP00000545637.1

Frequencies

GnomAD3 genomes

AF:

0.000202

AC:

AN:

133408

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000576

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000160

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000363

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000165

AC:

AN:

188230

AF XY:

0.000204

show subpopulations

Gnomad AFR exome

AF:

0.000153

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000165

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000295

Gnomad OTH exome

AF:

0.000227

GnomAD4 exome

AF:

0.000421

AC:

536

AN:

1273292

Hom.:

Cov.:

AF XY:

0.000426

AC XY:

268

AN XY:

629542

show subpopulations

African (AFR)

AF:

0.0000351

AC:

AN:

28462

American (AMR)

AF:

0.0000989

AC:

AN:

30338

Ashkenazi Jewish (ASJ)

AF:

0.000141

AC:

AN:

21268

East Asian (EAS)

AF:

0.00

AC:

AN:

37822

South Asian (SAS)

AF:

0.0000293

AC:

AN:

68266

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49518

Middle Eastern (MID)

AF:

0.000195

AC:

AN:

5140

European-Non Finnish (NFE)

AF:

0.000504

AC:

494

AN:

979614

Other (OTH)

AF:

0.000605

AC:

AN:

52864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000202

AC:

AN:

133408

Hom.:

Cov.:

AF XY:

0.000126

AC XY:

AN XY:

63582

show subpopulations

African (AFR)

AF:

0.0000576

AC:

AN:

34726

American (AMR)

AF:

0.000160

AC:

AN:

12506

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3278

East Asian (EAS)

AF:

0.00

AC:

AN:

4594

South Asian (SAS)

AF:

0.00

AC:

AN:

3674

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000363

AC:

AN:

63324

Other (OTH)

AF:

0.00

AC:

AN:

1728

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000289

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000483

AC:

ExAC

AF:

0.000125

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.71

M_CAP

Benign

0.0063

MetaRNN

Benign

0.20

MetaSVM

Uncertain

-0.23

PhyloP100

2.8

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.14

Sift

Benign

0.10

Sift4G

Benign

0.079

Polyphen

1.0

Vest4

0.11

MVP

0.20

MPC

0.66

ClinPred

0.19

GERP RS

5.6

Varity_R

0.15

gMVP

0.25

Mutation Taster

=78/22

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over