rs201999820

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BS1_Supporting

The NM_001080510.5(METTL23):c.20C>T(p.Ala7Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,598,740 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 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

METTL23
NM_001080510.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.48

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

intellectual disability, autosomal recessive 44
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

METTL23 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.794

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000332 (480/1446530) while in subpopulation NFE AF = 0.000431 (476/1103454). AF 95% confidence interval is 0.000399. There are 0 homozygotes in GnomAdExome4. There are 224 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. 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.20C>T	p.Ala7Val	missense_variant	Exon 2 of 5	ENST00000341249.11	NP_001073979.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METTL23	ENST00000341249.11 link	c.20C>T	p.Ala7Val	missense_variant	Exon 2 of 5	1	NM_001080510.5	ENSP00000341543.5

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000115

AC:

AN:

226166

AF XY:

0.0000900

show subpopulations

Gnomad AFR exome

AF:

0.000143

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000230

Gnomad OTH exome

AF:

0.000176

GnomAD4 exome

AF:

0.000332

AC:

480

AN:

1446530

Hom.:

Cov.:

AF XY:

0.000312

AC XY:

224

AN XY:

717984

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33310

American (AMR)

AF:

0.00

AC:

AN:

42662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25824

East Asian (EAS)

AF:

0.00

AC:

AN:

39412

South Asian (SAS)

AF:

0.00

AC:

AN:

83684

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000431

AC:

476

AN:

1103454

Other (OTH)

AF:

0.0000501

AC:

AN:

59848

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.0000920

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41446

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.000224

Hom.:

Bravo

AF:

0.000128

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000604

AC:

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 44

Uncertain:2

Jul 31, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Apr 27, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Oct 25, 2015

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Mar 11, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign in association with METTL23-related neurodevelopmental disorder to our knowledge, but has been reported in the heterozygous state in two siblings with normal-tension glaucoma (PMID: 39325437); This variant is associated with the following publications: (PMID: 39325437) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

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

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.072

MetaRNN

Pathogenic

0.79

D;D;D;D;D;D;D

MetaSVM

Benign

-0.69

MutationAssessor

Pathogenic

4.1

.;H;.;.;.;.;H

PhyloP100

7.5

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.8

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

REVEL

Uncertain

0.55

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.0030

D;D;D;D;D;D;D

Polyphen

0.99

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

Vest4

0.83

MVP

0.60

MPC

0.0011

ClinPred

0.93

GERP RS

5.7

Varity_R

0.96

gMVP

0.78

Mutation Taster

=30/70

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over