17-76733159-T-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_001080510.5(METTL23):c.266T>A(p.Leu89Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,613,968 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 0.00032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

METTL23
NM_001080510.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.65

Variant links:

Genes affected

METTL23 (HGNC:26988): (methyltransferase 23, arginine) The protein encoded by this gene functions as a transcription factor regulator in the transcriptional pathway for human cognition. It is a partner of the alpha subunit of the GA-binding protein transcription factor. Mutations in this gene cause mild autosomal recessive intellectual disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

METTL23 links:

ENSG00000267168 (HGNC:):

ENSG00000267168 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1245164).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000322 (49/152370) while in subpopulation AFR AF= 0.00113 (47/41598). AF 95% confidence interval is 0.000873. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL23	NM_001080510.5 link	c.266T>A	p.Leu89Gln	missense_variant	Exon 3 of 5	ENST00000341249.11	NP_001073979.3	Q86XA0-1A0A024R8M5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METTL23	ENST00000341249.11 link	c.266T>A	p.Leu89Gln	missense_variant	Exon 3 of 5	1	NM_001080510.5	ENSP00000341543.5		Q86XA0-1
ENSG00000267168	ENST00000587459.1 link	c.182T>A	p.Leu61Gln	missense_variant	Exon 1 of 2	5		ENSP00000466829.1		K7EN84

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000108

AC:

AN:

248936

Hom.:

AF XY:

0.0000963

AC XY:

AN XY:

135048

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.000145

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:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461598

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.000836

Gnomad4 AMR exome

AF:

0.000134

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:

0.00000450

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000322

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.000131

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

Alfa

AF:

0.000166

Hom.:

Bravo

AF:

0.000393

ESP6500AA

AF:

0.000264

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000993

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 44

Uncertain:2

Wangler Lab, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense METTL23 variant at c.266T>A (p.L89Q) was seen on exome through the Texome project (R01HG011795). This variant has been observed in gnomAD with a frequency of 0.010% in heterozygotes and has not been observed in the homozygous state (PM2). It has an inconclusive CADD score (25.000) with high conservation. We classify this as a variant of uncertain significance. -

Mar 23, 2022

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.023

.;T;.;.;.;.;.;.;.;.;T;.;.;.

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D;D;D;.;D;D;.;D;.;.;D;D;D

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.12

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Pathogenic

3.2

.;M;.;.;.;.;.;.;.;.;M;.;.;.

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-4.7

.;.;.;.;.;.;.;.;.;.;D;.;.;.

REVEL

Uncertain

0.45

Sift

Uncertain

0.0090

.;.;.;.;.;.;.;.;.;.;D;.;.;.

Sift4G

Benign

0.15

T;T;D;T;T;T;T;D;D;D;T;D;D;D

Polyphen

1.0

.;D;.;.;.;.;.;.;.;.;D;.;.;.

Vest4

0.57

MVP

0.59

MPC

0.0010

ClinPred

0.24

GERP RS

6.2

Varity_R

0.68

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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