rs147321492

Positions:

• chr17-76733682-T-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.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. 13/20 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.388

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]

ENSG00000267168 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
METTL23	NM_001080510.5	c.569T>C	p.Leu190Pro	missense_variant	5/5	ENST00000341249.11	NP_001073979.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
METTL23	ENST00000341249.11	c.569T>C	p.Leu190Pro	missense_variant	5/5	1	NM_001080510.5	ENSP00000341543.5
ENSG00000267168	ENST00000587459.1	c.238+467T>C		intron_variant		5		ENSP00000466829.1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 572 AN: 152136 Hom.: 5 Cov.: 33

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

GnomAD3 exomes AF: 0.00500 AC: 1238 AN: 247570 Hom.: 10 AF XY: 0.00482 AC XY: 648 AN XY: 134368

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 SAS exome AF: 0.00178

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.: 36 Cov.: 33 AF XY: 0.00457 AC XY: 3322 AN XY: 726382

Gnomad4 AFR exome AF: 0.000808

Gnomad4 AMR exome AF: 0.000787

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00153

Gnomad4 FIN exome AF: 0.0229

Gnomad4 NFE exome AF: 0.00470

Gnomad4 OTH exome AF: 0.00375

GnomAD4 genome AF: 0.00376 AC: 573 AN: 152252 Hom.: 5 Cov.: 33 AF XY: 0.00439 AC XY: 327 AN XY: 74456

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0214

Gnomad4 NFE AF: 0.00421

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00368 Hom.: 1

Bravo AF: 0.00213

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00104 AC: 4

ESP6500EA AF: 0.00495 AC: 41

ExAC AF: 0.00449 AC: 542

Asia WGS AF: 0.000289 AC: 1 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

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	METTL23: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 04, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0039	T;.;.;T;.;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.67	T;.;.;.;T;T
MetaRNN	Benign	0.0037	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;.;N;.;.
PrimateAI	Benign	0.36	T
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	T
GERP RS		1.5
Varity_R		0.11
gMVP		0.85

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

LitVar

Other links and lift over

dbSNP: rs147321492; hg19: chr17-74729764; COSMIC: COSV57974346; COSMIC: COSV57974346;