rs147321492

Variant names:

• chr17-76733682-T-C
• rs147321492
• NM_001080510.5:c.569T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080510.5(METTL23):​c.569T>C​(p.Leu190Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,612,436 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (36 hom.)
• Consequence: METTL23 NM_001080510.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.388
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036555827).
• BP6: Variant 17-76733682-T-C is Benign according to our data. Variant chr17-76733682-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 425145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00376 (573/152252) while in subpopulation NFE AF = 0.00421 (286/68010). AF 95% confidence interval is 0.0038. There are 5 homozygotes in GnomAd4. There are 327 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.569T>C	p.Leu190Pro	missense	Exon 5 of 5	NP_001073979.3	Q86XA0-1
	METTL23	NM_001206983.3		c.569T>C	p.Leu190Pro	missense	Exon 5 of 5	NP_001193912.1	Q86XA0-1
	METTL23	NM_001206984.3		c.569T>C	p.Leu190Pro	missense	Exon 5 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.569T>C	p.Leu190Pro	missense	Exon 5 of 5	ENSP00000341543.5	Q86XA0-1
	METTL23	ENST00000590964.5	TSL:1	c.368T>C	p.Leu123Pro	missense	Exon 4 of 4	ENSP00000465890.1	Q86XA0-2
	METTL23	ENST00000586200.1	TSL:1	c.212T>C	p.Leu71Pro	missense	Exon 3 of 3	ENSP00000465959.1	K7EL83

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 572 AN: 152136 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00420

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00500 AC: 1238 AN: 247570 AF XY: 0.00482

Gnomad AFR exome AF: 0.000712

Gnomad AMR exome AF: 0.000701

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.0243

Gnomad NFE exome AF: 0.00547

Gnomad OTH exome AF: 0.00284

GnomAD4 exome AF: 0.00470 AC: 6868 AN: 1460184 Hom.: 36 Cov.: 33 AF XY: 0.00457 AC XY: 3322 AN XY: 726382

African (AFR) AF: 0.000808 AC: 27 AN: 33396

American (AMR) AF: 0.000787 AC: 35 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26046

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00153 AC: 132 AN: 86038

European-Finnish (FIN) AF: 0.0229 AC: 1217 AN: 53200

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.00470 AC: 5227 AN: 1111254

Other (OTH) AF: 0.00375 AC: 226 AN: 60312

GnomAD4 genome AF: 0.00376 AC: 573 AN: 152252 Hom.: 5 Cov.: 33 AF XY: 0.00439 AC XY: 327 AN XY: 74456

African (AFR) AF: 0.000867 AC: 36 AN: 41544

American (AMR) AF: 0.000916 AC: 14 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.0214 AC: 227 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00421 AC: 286 AN: 68010

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00345 Hom.: 1

Bravo AF: 0.00213

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00104 AC: 4

ESP6500EA AF: 0.00495 AC: 41

ExAC AF: 0.00449 AC: 542

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00403

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.39
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.056
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.13
MVP		0.30
MPC		0.00061
ClinPred		0.029	T
GERP RS		1.5
Varity_R		0.11
gMVP		0.85
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147321492; hg19: chr17-74729764; COSMIC: COSV57974346; COSMIC: COSV57974346;