17-76733029-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.772

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]

ACMG classification

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 GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
METTL23	NM_001080510.5	c.136G>C	p.Glu46Gln	missense_variant	3/5	ENST00000341249.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
METTL23	ENST00000341249.11	c.136G>C	p.Glu46Gln	missense_variant	3/5	1	NM_001080510.5	P1

Frequencies

GnomAD3 genomes AF: 0.00683 AC: 1039 AN: 152202 Hom.: 12 Cov.: 33

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.: 6 AF XY: 0.00125 AC XY: 152 AN XY: 121286

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.: 11 Cov.: 33 AF XY: 0.000601 AC XY: 431 AN XY: 717724

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.: 12 Cov.: 33 AF XY: 0.00687 AC XY: 512 AN XY: 74484

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.: 2

Bravo AF: 0.00789

ESP6500AA AF: 0.0195 AC: 75

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00183 AC: 221

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

METTL23-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2019

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	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.54
Dann	Benign	0.62
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.33	N
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	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.22	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	T
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

Other links and lift over

dbSNP: rs114299201; hg19: chr17-74729111; COSMIC: COSV57976508; COSMIC: COSV57976508;