rs746453662

Variant names:

• chr17-76733063-ACTGT-A
• rs746453662
• NM_001080510.5:c.174_177delTCTG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001080510.5(METTL23):​c.174_177delTCTG​(p.Cys58TrpfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000647 in 1,606,928 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: METTL23 NM_001080510.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.63
• Publications: 0 publications found

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000267168 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 17-76733063-ACTGT-A is Pathogenic according to our data. Variant chr17-76733063-ACTGT-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 985456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080510.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METTL23	NM_001080510.5	MANE Select	c.174_177delTCTG	p.Cys58TrpfsTer10	frameshift	Exon 3 of 5	NP_001073979.3	Q86XA0-1
	METTL23	NM_001206983.3		c.174_177delTCTG	p.Cys58TrpfsTer10	frameshift	Exon 3 of 5	NP_001193912.1	Q86XA0-1
	METTL23	NM_001206984.3		c.174_177delTCTG	p.Cys58TrpfsTer10	frameshift	Exon 3 of 5	NP_001193913.1	Q86XA0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METTL23	ENST00000341249.11	TSL:1 MANE Select	c.174_177delTCTG	p.Cys58TrpfsTer10	frameshift	Exon 3 of 5	ENSP00000341543.5	Q86XA0-1
	ENSG00000267168	ENST00000587459.1	TSL:5	c.90_93delTCTG	p.Cys30TrpfsTer10	frameshift	Exon 1 of 2	ENSP00000466829.1	K7EN84
	METTL23	ENST00000590964.5	TSL:1	c.-28_-25delTCTG		5_prime_UTR	Exon 2 of 4	ENSP00000465890.1	Q86XA0-2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000420 AC: 10 AN: 237844 AF XY: 0.0000466

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000839

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.0000687 AC: 100 AN: 1454780 Hom.: 0 AF XY: 0.0000498 AC XY: 36 AN XY: 723074

African (AFR) AF: 0.0000299 AC: 1 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 43520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25936

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 85050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000830 AC: 92 AN: 1108324

Other (OTH) AF: 0.0000665 AC: 4 AN: 60142

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability, autosomal recessive 44 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs746453662; hg19: chr17-74729145;