17-76733068-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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.

• 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

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 Uncertain_significance. Variant got 1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL23	NM_001080510.5	c.175C>G	p.Leu59Val	missense_variant	Exon 3 of 5	ENST00000341249.11	NP_001073979.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METTL23	ENST00000341249.11	c.175C>G	p.Leu59Val	missense_variant	Exon 3 of 5	1	NM_001080510.5	ENSP00000341543.5
ENSG00000267168	ENST00000587459.1	c.91C>G	p.Leu31Val	missense_variant	Exon 1 of 2	5		ENSP00000466829.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;.;.;.;T;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;.;D;D;.;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;L;.;.;.;.;L;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.4	.;.;.;.;.;.;N;.
REVEL	Benign	0.25
Sift	Uncertain	0.0050	.;.;.;.;.;.;D;.
Sift4G	Uncertain	0.020	D;D;D;D;D;D;D;D
Polyphen		0.99	.;D;.;.;.;.;D;.
Vest4		0.67
MutPred		0.61		Loss of catalytic residue at L59 (P = 0.022);Loss of catalytic residue at L59 (P = 0.022);Loss of catalytic residue at L59 (P = 0.022);Loss of catalytic residue at L59 (P = 0.022);Loss of catalytic residue at L59 (P = 0.022);Loss of catalytic residue at L59 (P = 0.022);Loss of catalytic residue at L59 (P = 0.022);.;
MVP		0.35
MPC		0.0010
ClinPred		0.88	D
GERP RS		3.9
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

Publications

LitVar

Other links and lift over

dbSNP: rs12602772; hg19: chr17-74729150;