chr17-76733159-T-A

Position:

• chr17-76733159-T-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_001080510.5(METTL23):​c.266T>A​(p.Leu89Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: METTL23 NM_001080510.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.65

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1245164).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000322 (49/152370) while in subpopulation AFR AF= 0.00113 (47/41598). AF 95% confidence interval is 0.000873. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
METTL23	NM_001080510.5	c.266T>A	p.Leu89Gln	missense_variant	3/5	ENST00000341249.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
METTL23	ENST00000341249.11	c.266T>A	p.Leu89Gln	missense_variant	3/5	1	NM_001080510.5	P1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 248936 Hom.: 0 AF XY: 0.0000963 AC XY: 13 AN XY: 135048

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461598 Hom.: 0 Cov.: 33 AF XY: 0.0000261 AC XY: 19 AN XY: 727060

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.000134

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: 0.00000450

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152370 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74520

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.000131

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: 0.00

Alfa AF: 0.000166 Hom.: 0

Bravo AF: 0.000393

ESP6500AA AF: 0.000264 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000993 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal recessive 44 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 23, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Wangler Lab, Baylor College of Medicine	-	This missense METTL23 variant at c.266T>A (p.L89Q) was seen on exome through the Texome project (R01HG011795). This variant has been observed in gnomAD with a frequency of 0.010% in heterozygotes and has not been observed in the homozygous state (PM2). It has an inconclusive CADD score (25.000) with high conservation. We classify this as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	.;T;.;.;.;.;.;.;.;.;T;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D;.;D;D;.;D;.;.;D;D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	3.2	.;M;.;.;.;.;.;.;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.7	.;.;.;.;.;.;.;.;.;.;D;.;.;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.0090	.;.;.;.;.;.;.;.;.;.;D;.;.;.
Sift4G	Benign	0.15	T;T;D;T;T;T;T;D;D;D;T;D;D;D
Polyphen		1.0	.;D;.;.;.;.;.;.;.;.;D;.;.;.
Vest4		0.57
MVP		0.59
MPC		0.0010
ClinPred		0.24	T
GERP RS		6.2
Varity_R		0.68
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs373560298; hg19: chr17-74729241;