rs773937309

Variant names:

• chr17-76733165-TACC-T
• rs773937309
• NM_001080510.5:c.278_280delCAC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4_Supporting PP5

The NM_001080510.5(METTL23):​c.278_280delCAC​(p.Pro93del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: METTL23 NM_001080510.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 7.55
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001080510.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 17-76733165-TACC-T is Pathogenic according to our data. Variant chr17-76733165-TACC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 520855.

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.278_280delCAC	p.Pro93del	disruptive_inframe_deletion	Exon 3 of 5	NP_001073979.3	Q86XA0-1
	METTL23	NM_001206983.3		c.278_280delCAC	p.Pro93del	disruptive_inframe_deletion	Exon 3 of 5	NP_001193912.1	Q86XA0-1
	METTL23	NM_001206984.3		c.278_280delCAC	p.Pro93del	disruptive_inframe_deletion	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.278_280delCAC	p.Pro93del	disruptive_inframe_deletion	Exon 3 of 5	ENSP00000341543.5	Q86XA0-1
	METTL23	ENST00000590964.5	TSL:1	c.77_79delCAC	p.Pro26del	disruptive_inframe_deletion	Exon 2 of 4	ENSP00000465890.1	Q86XA0-2
	ENSG00000267168	ENST00000587459.1	TSL:5	c.194_196delCAC	p.Pro65del	disruptive_inframe_deletion	Exon 1 of 2	ENSP00000466829.1	K7EN84

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000191

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000100 AC: 25 AN: 248960 AF XY: 0.0000962

Gnomad AFR exome AF: 0.000259

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: 0.000151

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000156 AC: 228 AN: 1461604 Hom.: 0 AF XY: 0.000166 AC XY: 121 AN XY: 727062

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000192 AC: 214 AN: 1111834

Other (OTH) AF: 0.0000828 AC: 5 AN: 60374

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74510

African (AFR) AF: 0.000144 AC: 6 AN: 41592

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000959 Hom.: 0

Bravo AF: 0.000106

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	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		7.5
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs773937309; hg19: chr17-74729247;