Genetic Variant METTL25B:p.Arg127Gln (chr1-156732424-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015997.4(METTL25B):c.380G>A(p.Arg127Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000646 in 1,614,140 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00063 ( 0 hom. )

Consequence

METTL25B
NM_015997.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.93

Publications

4 publications found

Variant links:

Genes affected

METTL25B (HGNC:24273): (methyltransferase like 25B) Predicted to enable rRNA (adenine-N6,N6-)-dimethyltransferase activity. Predicted to be involved in rRNA methylation. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

METTL25B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026885182).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015997.4. 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
	METTL25B	NM_015997.4	MANE Select	c.380G>A	p.Arg127Gln	missense	Exon 3 of 8	NP_057081.3
	METTL25B	NM_001142560.2		c.380G>A	p.Arg127Gln	missense	Exon 3 of 7	NP_001136032.1	Q96FB5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
METTL25B	ENST00000368216.9	TSL:1 MANE Select	c.380G>A	p.Arg127Gln	missense	Exon 3 of 8	ENSP00000357199.4	Q96FB5-1
METTL25B	ENST00000917461.1		c.380G>A	p.Arg127Gln	missense	Exon 3 of 8	ENSP00000587520.1
METTL25B	ENST00000892486.1		c.380G>A	p.Arg127Gln	missense	Exon 3 of 8	ENSP00000562545.1

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000689

AC:

173

AN:

251088

AF XY:

0.000685

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.00190

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.00100

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000630

AC:

921

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

459

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000581

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000459

AC:

AN:

26136

East Asian (EAS)

AF:

0.00121

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000703

AC:

782

AN:

1112010

Other (OTH)

AF:

0.000762

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

105

158

210

263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000801

AC:

122

AN:

152278

Hom.:

Cov.:

AF XY:

0.000725

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41558

American (AMR)

AF:

0.00196

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68018

Other (OTH)

AF:

0.00190

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.00106

Hom.:

Bravo

AF:

0.000979

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000692

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.000771

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

Uncertain

0.41

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.050

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.028

MetaRNN

Benign

0.027

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.4

PhyloP100

8.9

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-2.0

REVEL

Benign

0.23

Sift

Uncertain

0.028

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.57

MVP

0.72

MPC

0.80

ClinPred

0.12

GERP RS

4.8

PromoterAI

-0.092

Neutral

(source)

Varity_R

0.41

gMVP

0.59

Mutation Taster

=52/48

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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