Genetic Variant METTL25B:p.Tyr28Cys (chr1-156729187-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_015997.4(METTL25B):c.83A>G(p.Tyr28Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,606,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

METTL25B
NM_015997.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.75

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 made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL25B	NM_015997.4 link	c.83A>G	p.Tyr28Cys	missense_variant	Exon 1 of 8	ENST00000368216.9	NP_057081.3	Q96FB5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
METTL25B	ENST00000368216.9 link	c.83A>G	p.Tyr28Cys	missense_variant	Exon 1 of 8	1	NM_015997.4	ENSP00000357199.4	Q96FB5-1
METTL25B	ENST00000519086.5 link	c.83A>G	p.Tyr28Cys	missense_variant	Exon 1 of 5	3		ENSP00000429756.1	E5RHI7
METTL25B	ENST00000368218.8 link	c.83A>G	p.Tyr28Cys	missense_variant	Exon 1 of 7	3		ENSP00000357201.4	Q96FB5-2
METTL25B	ENST00000524343.1 link	c.83A>G	p.Tyr28Cys	missense_variant	Exon 1 of 3	5		ENSP00000429389.1	E5RIL6

Frequencies

GnomAD3 genomes

AF:

0.0000402

AC:

AN:

149390

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000494

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000445

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000203

AC:

AN:

246908

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

133762

show subpopulations

Gnomad AFR exome

AF:

0.000128

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000112

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000894

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000824

AC:

AN:

1456974

Hom.:

Cov.:

AF XY:

0.00000966

AC XY:

AN XY:

724820

show subpopulations

Gnomad4 AFR exome

AF:

0.0000303

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000721

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000401

AC:

AN:

149510

Hom.:

Cov.:

AF XY:

0.0000412

AC XY:

AN XY:

72734

show subpopulations

Gnomad4 AFR

AF:

0.0000493

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000197

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000445

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.83A>G (p.Y28C) alteration is located in exon 1 (coding exon 1) of the RRNAD1 gene. This alteration results from a A to G substitution at nucleotide position 83, causing the tyrosine (Y) at amino acid position 28 to be replaced by a cysteine (C). 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

0.23

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.30

.;T;T;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.82

T;T;T;T

M_CAP

Benign

0.032

MetaRNN

Pathogenic

0.78

D;D;D;D

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.5

M;M;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-6.6

D;D;D;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.56

MVP

0.72

MPC

0.26

ClinPred

0.70

GERP RS

4.6

Varity_R

0.77

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over