rs147321492

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001080510.5(METTL23):c.569T>C(p.Leu190Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,612,436 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0047 ( 36 hom. )

Consequence

METTL23
NM_001080510.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.388

Publications

8 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:

ENSG00000267168 (HGNC:):

ENSG00000267168 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036555827).

BP6

Variant 17-76733682-T-C is Benign according to our data. Variant chr17-76733682-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 425145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00376 (573/152252) while in subpopulation NFE AF = 0.00421 (286/68010). AF 95% confidence interval is 0.0038. There are 5 homozygotes in GnomAd4. There are 327 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL23	NM_001080510.5 link	c.569T>C	p.Leu190Pro	missense_variant	Exon 5 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.569T>C	p.Leu190Pro	missense_variant	Exon 5 of 5	1	NM_001080510.5	ENSP00000341543.5		Q86XA0-1
ENSG00000267168	ENST00000587459.1 link	c.238+467T>C		intron_variant	Intron 1 of 1	5		ENSP00000466829.1		K7EN84

Frequencies

GnomAD3 genomes

AF:

0.00376

AC:

572

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.0214

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00420

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00500

AC:

1238

AN:

247570

AF XY:

0.00482

show subpopulations

Gnomad AFR exome

AF:

0.000712

Gnomad AMR exome

AF:

0.000701

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000559

Gnomad FIN exome

AF:

0.0243

Gnomad NFE exome

AF:

0.00547

Gnomad OTH exome

AF:

0.00284

GnomAD4 exome

AF:

0.00470

AC:

6868

AN:

1460184

Hom.:

Cov.:

AF XY:

0.00457

AC XY:

3322

AN XY:

726382

show subpopulations

African (AFR)

AF:

0.000808

AC:

AN:

33396

American (AMR)

AF:

0.000787

AC:

AN:

44490

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26046

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.00153

AC:

132

AN:

86038

European-Finnish (FIN)

AF:

0.0229

AC:

1217

AN:

53200

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00470

AC:

5227

AN:

1111254

Other (OTH)

AF:

0.00375

AC:

226

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

323

645

968

1290

1613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

392

588

784

980

<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:

0.00376

AC:

573

AN:

152252

Hom.:

Cov.:

AF XY:

0.00439

AC XY:

327

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000867

AC:

AN:

41544

American (AMR)

AF:

0.000916

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00124

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0214

AC:

227

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00421

AC:

286

AN:

68010

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

107

134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00345

Hom.:

Bravo

AF:

0.00213

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00495

AC:

ExAC

AF:

0.00449

AC:

542

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00403

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

METTL23: BP4, BS2 -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

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

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0039

T;.;.;T;.;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.67

T;.;.;.;T;T

MetaRNN

Benign

0.0037

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;.;.;N;.;.

PhyloP100

0.39

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.26

.;.;.;N;.;.

REVEL

Benign

0.056

Sift

Uncertain

0.0060

.;.;.;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

0.0

B;.;.;B;.;.

Vest4

0.13

MVP

0.30

MPC

.;.;.;6.13132820774E-4;.;.

ClinPred

0.029

GERP RS

1.5

Varity_R

0.11

gMVP

0.85

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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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