Genetic Variant METTL22:p.Ala219Thr (chr16-8635267-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_024109.4(METTL22):c.655G>A(p.Ala219Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 1,603,568 control chromosomes in the GnomAD database, including 53,780 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 3785 hom., cov: 33)

Exomes 𝑓: 0.26 ( 49995 hom. )

Consequence

METTL22
NM_024109.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.88

Publications

31 publications found

Variant links:

Genes affected

METTL22 (HGNC:28368): (methyltransferase 22, Kin17 lysine) This gene encodes a member of the non-histone lysine methyltransferases. It interacts with its substrate, Kin17, which is involved in DNA repair and replication and mRNA processing. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

METTL22 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070168376).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL22	NM_024109.4 link	c.655G>A	p.Ala219Thr	missense_variant	Exon 5 of 11	ENST00000381920.8	NP_077014.4	Q9BUU2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METTL22	ENST00000381920.8 link	c.655G>A	p.Ala219Thr	missense_variant	Exon 5 of 11	5	NM_024109.4	ENSP00000371345.3		Q9BUU2-1

Frequencies

GnomAD3 genomes

AF:

0.196

AC:

29771

AN:

151964

Hom.:

3785

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0554

Gnomad AMI

AF:

0.348

Gnomad AMR

AF:

0.181

Gnomad ASJ

AF:

0.0934

Gnomad EAS

AF:

0.356

Gnomad SAS

AF:

0.171

Gnomad FIN

AF:

0.237

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.271

Gnomad OTH

AF:

0.200

GnomAD2 exomes

AF:

0.223

AC:

54396

AN:

244294

AF XY:

0.224

show subpopulations

Gnomad AFR exome

AF:

0.0507

Gnomad AMR exome

AF:

0.149

Gnomad ASJ exome

AF:

0.0965

Gnomad EAS exome

AF:

0.370

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.269

Gnomad OTH exome

AF:

0.216

GnomAD4 exome

AF:

0.255

AC:

370453

AN:

1451486

Hom.:

49995

Cov.:

AF XY:

0.253

AC XY:

182320

AN XY:

720806

show subpopulations

African (AFR)

AF:

0.0444

AC:

1482

AN:

33356

American (AMR)

AF:

0.154

AC:

6840

AN:

44280

Ashkenazi Jewish (ASJ)

AF:

0.0958

AC:

2481

AN:

25890

East Asian (EAS)

AF:

0.347

AC:

13710

AN:

39502

South Asian (SAS)

AF:

0.160

AC:

13670

AN:

85684

European-Finnish (FIN)

AF:

0.243

AC:

12186

AN:

50220

Middle Eastern (MID)

AF:

0.134

AC:

759

AN:

5646

European-Non Finnish (NFE)

AF:

0.276

AC:

305241

AN:

1106940

Other (OTH)

AF:

0.235

AC:

14084

AN:

59968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

14664

29329

43993

58658

73322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10070

20140

30210

40280

50350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.196

AC:

29768

AN:

152082

Hom.:

3785

Cov.:

AF XY:

0.196

AC XY:

14567

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.0555

AC:

2302

AN:

41512

American (AMR)

AF:

0.181

AC:

2766

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0934

AC:

324

AN:

3468

East Asian (EAS)

AF:

0.356

AC:

1836

AN:

5156

South Asian (SAS)

AF:

0.171

AC:

823

AN:

4818

European-Finnish (FIN)

AF:

0.237

AC:

2505

AN:

10574

Middle Eastern (MID)

AF:

0.134

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.271

AC:

18436

AN:

67966

Other (OTH)

AF:

0.199

AC:

420

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1178

2356

3533

4711

5889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

316

632

948

1264

1580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.239

Hom.:

14783

Bravo

AF:

0.187

TwinsUK

AF:

0.262

AC:

972

ALSPAC

AF:

0.283

AC:

1092

ESP6500AA

AF:

0.0589

AC:

240

ESP6500EA

AF:

0.255

AC:

2143

ExAC

AF:

0.223

AC:

26995

Asia WGS

AF:

0.240

AC:

834

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.70

CADD

Benign

6.0

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.00085

T;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.0070

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.24

N;.

PhyloP100

1.9

PrimateAI

Benign

0.32

PROVEAN

Benign

0.070

N;N

REVEL

Benign

0.013

Sift

Benign

0.62

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.012

B;.

Vest4

0.096

MPC

0.016

ClinPred

0.0088

GERP RS

-0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.025

gMVP

0.44

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over