chr17-76733029-G-A

Variant names:

• chr17-76733029-G-A
• rs114299201
• NM_001080510.5:c.136G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001080510.5(METTL23):​c.136G>A​(p.Glu46Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,445,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E46Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: METTL23 NM_001080510.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.772

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03297755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL23	NM_001080510.5	c.136G>A	p.Glu46Lys	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.136G>A	p.Glu46Lys	missense_variant	Exon 3 of 5	1	NM_001080510.5	ENSP00000341543.5
ENSG00000267168	ENST00000587459.1	c.52G>A	p.Glu18Lys	missense_variant	Exon 1 of 2	5		ENSP00000466829.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000890 AC: 2 AN: 224662 Hom.: 0 AF XY: 0.0000165 AC XY: 2 AN XY: 121286

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000609

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000178

GnomAD4 exome AF: 0.00000415 AC: 6 AN: 1445872 Hom.: 0 Cov.: 33 AF XY: 0.00000836 AC XY: 6 AN XY: 717724

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000357

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.70
DANN	Benign	0.65
DEOGEN2	Benign	0.00099	.;T;.;.;.;.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.87	D;T;D;.;D;D;.;D
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.033	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.36	.;N;.;.;.;.;N;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.10	.;.;.;.;.;.;N;.
REVEL	Benign	0.0080
Sift	Benign	0.94	.;.;.;.;.;.;T;.
Sift4G	Benign	0.82	T;T;T;T;T;T;T;T
Polyphen		0.0	.;B;.;.;.;.;B;.
Vest4		0.18
MutPred		0.44		Gain of methylation at E46 (P = 0.0042);Gain of methylation at E46 (P = 0.0042);Gain of methylation at E46 (P = 0.0042);Gain of methylation at E46 (P = 0.0042);Gain of methylation at E46 (P = 0.0042);Gain of methylation at E46 (P = 0.0042);Gain of methylation at E46 (P = 0.0042);.;
MVP		0.27
MPC		.;.;.;.;.;.;6.86557160948E-4;.
ClinPred		0.018	T
GERP RS		-5.5
Varity_R		0.049
gMVP		0.40

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: rs114299201; hg19: chr17-74729111;