17-76733069-T-TG

Position:

• chr17-76733069-T-TG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001080510.5(METTL23):​c.178dup​(p.Glu60GlyfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L59L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: METTL23 NM_001080510.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.0440

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-76733069-T-TG is Pathogenic according to our data. Variant chr17-76733069-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 812707.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
METTL23	NM_001080510.5	c.178dup	p.Glu60GlyfsTer11	frameshift_variant	3/5	ENST00000341249.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
METTL23	ENST00000341249.11	c.178dup	p.Glu60GlyfsTer11	frameshift_variant	3/5	1	NM_001080510.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, autosomal recessive 44 Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Department of Medical Genetics, National Institute of Health	-	We report the NM_001080510.3(METTL23):c.176_177insG (p. Glu60fs) variant in two Moroccan siblings with mild intellectual disability and dysmorphic features (brachycephaly, prominent eyes, low set ears, a small short nose with hypoplasia of alae nasi and thin lips). Biallelic mutations in this gene have been reported to cause autosomal recessive mild intellectual disability. This mutation was homozygous in the affected siblings and their parents carry this mutation in heterozygous state. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 21, 2022	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1382444181; hg19: chr17-74729151;