rs12602772

Variant names:

• chr17-76733068-C-G
• rs12602772
• NM_001080510.5:c.175C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-76733068-C-G
• chr17-76733068-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001080510.5(METTL23):​c.175C>G​(p.Leu59Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L59L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: METTL23 NM_001080510.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41455388).

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.175C>G	p.Leu59Val	missense	Exon 3 of 5	NP_001073979.3	Q86XA0-1
	METTL23	NM_001206983.3		c.175C>G	p.Leu59Val	missense	Exon 3 of 5	NP_001193912.1	Q86XA0-1
	METTL23	NM_001206984.3		c.175C>G	p.Leu59Val	missense	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.175C>G	p.Leu59Val	missense	Exon 3 of 5	ENSP00000341543.5	Q86XA0-1
	ENSG00000267168	ENST00000587459.1	TSL:5	c.91C>G	p.Leu31Val	missense	Exon 1 of 2	ENSP00000466829.1	K7EN84
	METTL23	ENST00000590964.5	TSL:1	c.-27C>G		5_prime_UTR	Exon 2 of 4	ENSP00000465890.1	Q86XA0-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455982 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 723790

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 43682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 85208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109016

Other (OTH) AF: 0.0000166 AC: 1 AN: 60190

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.0
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.020	D
Polyphen		0.99	D
Vest4		0.67
MutPred		0.61		Loss of catalytic residue at L59 (P = 0.022)
MVP		0.35
MPC		0.0010
ClinPred		0.88	D
GERP RS		3.9
PromoterAI		0.0098	Neutral
Varity_R		0.83
gMVP		0.60

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: rs12602772; hg19: chr17-74729150;