Variant chr16-21599740-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016025.5(METTL9):c.7C>G(p.Leu3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 1,520,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000058 ( 0 hom. )

Consequence

METTL9
NM_016025.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.09

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03601846).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
METTL9	NM_016025.5 linkuse as main transcript	c.7C>G	p.Leu3Val	missense_variant	1/5	ENST00000358154.8
METTL9	NM_001077180.3 linkuse as main transcript	c.7C>G	p.Leu3Val	missense_variant	1/5
METTL9	NM_001288659.2 linkuse as main transcript	c.45+2440C>G		intron_variant
METTL9	NM_001288660.2 linkuse as main transcript	c.45+2440C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
METTL9	ENST00000358154.8 linkuse as main transcript	c.7C>G	p.Leu3Val	missense_variant	1/5	1	NM_016025.5	P3	Q9H1A3-1

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000211

AC:

AN:

142008

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

80720

show subpopulations

Gnomad AFR exome

AF:

0.000534

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000585

AC:

AN:

1368128

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

678656

show subpopulations

Gnomad4 AFR exome

AF:

0.000246

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000178

GnomAD4 genome

AF:

0.000145

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000132

ESP6500AA

AF:

0.00117

AC:

ESP6500EA

AF:

0.000139

AC:

ExAC

AF:

0.0000349

AC:

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

Mar 03, 2022

The c.7C>G (p.L3V) alteration is located in exon 1 (coding exon 1) of the METTL9 gene. This alteration results from a C to G substitution at nucleotide position 7, causing the leucine (L) at amino acid position 3 to be replaced by a valine (V). 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

0.071

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

T;.

Eigen

Benign

-0.0072

Eigen_PC

Benign

0.080

FATHMM_MKL

Benign

0.16

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.49

N;N

MutationTaster

Benign

0.94

N;N

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.18

N;N

REVEL

Benign

0.050

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.035

B;P

Vest4

0.17

MVP

0.67

MPC

0.92

ClinPred

0.23

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.30

gMVP

0.58

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