Variant 16-21612649-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_016025.5(METTL9):c.170A>T(p.Tyr57Phe) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000020 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

METTL9
NM_016025.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.69

Variant links:

Genes affected

METTL9 (HGNC:24586): (methyltransferase 9, His-X-His N1(pi)-histidine) Enables protein-L-histidine N-pros-methyltransferase activity. Predicted to be involved in methylation. Is active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

METTL9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
METTL9	NM_016025.5 linkuse as main transcript	c.170A>T	p.Tyr57Phe	missense_variant	2/5	ENST00000358154.8
METTL9	NM_001077180.3 linkuse as main transcript	c.170A>T	p.Tyr57Phe	missense_variant	2/5
METTL9	NM_001288659.2 linkuse as main transcript	c.50A>T	p.Tyr17Phe	missense_variant	2/5
METTL9	NM_001288660.2 linkuse as main transcript	c.50A>T	p.Tyr17Phe	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
METTL9	ENST00000358154.8 linkuse as main transcript	c.170A>T	p.Tyr57Phe	missense_variant	2/5	1	NM_016025.5	P3	Q9H1A3-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

120632

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000289

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000483

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000989

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000183

Gnomad OTH

AF:

0.000620

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000204

AC:

AN:

1177692

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

574008

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000665

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000200

Gnomad4 OTH exome

AF:

0.0000424

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000257

AC:

AN:

120694

Hom.:

Cov.:

AF XY:

0.000317

AC XY:

AN XY:

56814

show subpopulations

Gnomad4 AFR

AF:

0.000288

Gnomad4 AMR

AF:

0.000289

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000485

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000989

Gnomad4 NFE

AF:

0.000183

Gnomad4 OTH

AF:

0.000616

Alfa

AF:

0.00145

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.170A>T (p.Y57F) alteration is located in exon 2 (coding exon 2) of the METTL9 gene. This alteration results from a A to T substitution at nucleotide position 170, causing the tyrosine (Y) at amino acid position 57 to be replaced by a phenylalanine (F). 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

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Benign

0.89

DEOGEN2

Uncertain

0.47

.;T;.;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Uncertain

-0.20

MutationAssessor

Pathogenic

2.9

.;M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-3.2

D;D;D;.

REVEL

Pathogenic

0.66

Sift

Uncertain

0.017

D;D;D;.

Sift4G

Benign

0.095

T;T;T;T

Polyphen

1.0, 1.0

.;D;D;.

Vest4

0.65, 0.64, 0.69

MutPred

0.90

.;Gain of catalytic residue at Y57 (P = 0.1652);Gain of catalytic residue at Y57 (P = 0.1652);.;

MVP

0.83

MPC

1.8

ClinPred

0.85

GERP RS

6.0

Varity_R

0.38

gMVP

0.76

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

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