17-76733029-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001080510.5(METTL23):c.136G>C(p.Glu46Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,598,192 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 12 hom., cov: 33)

Exomes 𝑓: 0.00073 ( 11 hom. )

Consequence

METTL23
NM_001080510.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.772

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004484087).

BP6

Variant 17-76733029-G-C is Benign according to our data. Variant chr17-76733029-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 376858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-76733029-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00682 (1039/152320) while in subpopulation AFR AF= 0.0238 (989/41556). AF 95% confidence interval is 0.0226. There are 12 homozygotes in gnomad4. There are 512 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL23	NM_001080510.5 link	c.136G>C	p.Glu46Gln	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.136G>C	p.Glu46Gln	missense_variant	Exon 3 of 5	1	NM_001080510.5	ENSP00000341543.5		Q86XA0-1
ENSG00000267168	ENST00000587459.1 link	c.52G>C	p.Glu18Gln	missense_variant	Exon 1 of 2	5		ENSP00000466829.1		K7EN84

Frequencies

GnomAD3 genomes

AF:

0.00683

AC:

1039

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0238

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

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:

0.0000588

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00168

AC:

378

AN:

224662

Hom.:

AF XY:

0.00125

AC XY:

152

AN XY:

121286

show subpopulations

Gnomad AFR exome

AF:

0.0235

Gnomad AMR exome

AF:

0.00147

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:

0.0000300

Gnomad OTH exome

AF:

0.00160

GnomAD4 exome

AF:

0.000730

AC:

1055

AN:

1445872

Hom.:

Cov.:

AF XY:

0.000601

AC XY:

431

AN XY:

717724

show subpopulations

Gnomad4 AFR exome

AF:

0.0254

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000238

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000335

Gnomad4 OTH exome

AF:

0.00182

GnomAD4 genome

AF:

0.00682

AC:

1039

AN:

152320

Hom.:

Cov.:

AF XY:

0.00687

AC XY:

512

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0238

Gnomad4 AMR

AF:

0.00229

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00205

Hom.:

Bravo

AF:

0.00789

ESP6500AA

AF:

0.0195

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00183

AC:

221

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

METTL23-related disorder

Benign:1

Sep 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.54

DANN

Benign

0.62

DEOGEN2

Benign

0.0024

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

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.70

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

MetaRNN

Benign

0.0045

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

.;N;.;.;.;.;N;.

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.13

.;.;.;.;.;.;N;.

REVEL

Benign

0.0090

Sift

Benign

0.63

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

Sift4G

Benign

0.69

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

Polyphen

0.0020

.;B;.;.;.;.;B;.

Vest4

0.11

MVP

0.25

MPC

.;.;.;.;.;.;7.49502191348E-4;.

ClinPred

0.0015

GERP RS

-5.5

Varity_R

0.11

gMVP

0.34

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