chr17-76733081-G-C

Variant names:

• chr17-76733081-G-C
• rs373685308
• NM_001080510.5:c.188G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001080510.5(METTL23):​c.188G>C​(p.Arg63Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,610,218 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: METTL23 NM_001080510.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.777

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL23	NM_001080510.5	c.188G>C	p.Arg63Pro	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.188G>C	p.Arg63Pro	missense_variant	Exon 3 of 5	1	NM_001080510.5	ENSP00000341543.5
ENSG00000267168	ENST00000587459.1	c.104G>C	p.Arg35Pro	missense_variant	Exon 1 of 2	5		ENSP00000466829.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152082 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

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: 0.00

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458136 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 725026

Gnomad4 AFR exome AF: 0.000120

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152082 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74268

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000479

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	.;T;.;.;.;.;T;.
Eigen	Benign	-0.088
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D;D;D;.;D;D;.;D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	3.4	.;M;.;.;.;.;M;.
PrimateAI	Benign	0.20	T
PROVEAN	Pathogenic	-4.7	.;.;.;.;.;.;D;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0060	.;.;.;.;.;.;D;.
Sift4G	Uncertain	0.059	T;D;T;T;T;D;D;D
Polyphen		0.96	.;D;.;.;.;.;D;.
Vest4		0.70
MutPred		0.61		Loss of catalytic residue at R63 (P = 0.2314);Loss of catalytic residue at R63 (P = 0.2314);Loss of catalytic residue at R63 (P = 0.2314);Loss of catalytic residue at R63 (P = 0.2314);Loss of catalytic residue at R63 (P = 0.2314);Loss of catalytic residue at R63 (P = 0.2314);Loss of catalytic residue at R63 (P = 0.2314);.;
MVP		0.36
MPC		.;.;.;.;.;.;7.28519500863E-4;.
ClinPred		0.98	D
GERP RS		-5.1
Varity_R		0.86
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs373685308; hg19: chr17-74729163;