dbSNP rs10502302: METTL4:c.830-123C>T (chr18-2552887-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_022840.5(METTL4):c.830-123C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 628,238 control chromosomes in the GnomAD database, including 48,611 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.33 ( 9795 hom., cov: 32)

Exomes 𝑓: 0.39 ( 38816 hom. )

Consequence

METTL4
NM_022840.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.565

Publications

5 publications found

Variant links:

Genes affected

METTL4 (HGNC:24726): (methyltransferase 4, N6-adenosine) Enables RNA methyltransferase activity and site-specific DNA-methyltransferase (adenine-specific) activity. Involved in nucleic acid metabolic process; regulation of RNA metabolic process; and regulation of mitochondrial DNA replication. Located in cytosol; mitochondrial matrix; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

METTL4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022840.5. 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
	METTL4	NM_022840.5	MANE Select	c.830-123C>T		intron	N/A	NP_073751.3
	METTL4	NM_001308401.2		c.830-123C>T		intron	N/A	NP_001295330.1	J3KNJ7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
METTL4	ENST00000574538.2	TSL:1 MANE Select	c.830-123C>T	intron	N/A	ENSP00000458290.1	Q8N3J2
METTL4	ENST00000573134.1	TSL:1	n.3008C>T	non_coding_transcript_exon	Exon 3 of 7
METTL4	ENST00000919555.1		c.827-123C>T	intron	N/A	ENSP00000589614.1

Frequencies

GnomAD3 genomes

AF:

0.330

AC:

50109

AN:

151866

Hom.:

9786

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.313

Gnomad AMR

AF:

0.474

Gnomad ASJ

AF:

0.305

Gnomad EAS

AF:

0.633

Gnomad SAS

AF:

0.413

Gnomad FIN

AF:

0.435

Gnomad MID

AF:

0.324

Gnomad NFE

AF:

0.378

Gnomad OTH

AF:

0.336

GnomAD4 exome

AF:

0.392

AC:

186913

AN:

476254

Hom.:

38816

Cov.:

AF XY:

0.393

AC XY:

100294

AN XY:

255196

show subpopulations

African (AFR)

AF:

0.119

AC:

1522

AN:

12808

American (AMR)

AF:

0.540

AC:

10796

AN:

19994

Ashkenazi Jewish (ASJ)

AF:

0.288

AC:

4238

AN:

14696

East Asian (EAS)

AF:

0.620

AC:

19216

AN:

31008

South Asian (SAS)

AF:

0.411

AC:

19344

AN:

47028

European-Finnish (FIN)

AF:

0.414

AC:

13925

AN:

33602

Middle Eastern (MID)

AF:

0.340

AC:

1229

AN:

3620

European-Non Finnish (NFE)

AF:

0.371

AC:

106382

AN:

286484

Other (OTH)

AF:

0.380

AC:

10261

AN:

27014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

5114

10229

15343

20458

25572

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

666

1332

1998

2664

3330

<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:

0.330

AC:

50133

AN:

151984

Hom.:

9795

Cov.:

AF XY:

0.339

AC XY:

25138

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.125

AC:

5191

AN:

41460

American (AMR)

AF:

0.475

AC:

7267

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.305

AC:

1059

AN:

3470

East Asian (EAS)

AF:

0.632

AC:

3277

AN:

5182

South Asian (SAS)

AF:

0.415

AC:

2001

AN:

4820

European-Finnish (FIN)

AF:

0.435

AC:

4579

AN:

10520

Middle Eastern (MID)

AF:

0.305

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.378

AC:

25678

AN:

67932

Other (OTH)

AF:

0.335

AC:

707

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1588

3176

4763

6351

7939

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

502

1004

1506

2008

2510

<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:

0.357

Hom.:

1913

Bravo

AF:

0.329

Asia WGS

AF:

0.473

AC:

1646

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.3

(source)

DANN

Benign

0.53

PhyloP100

0.56

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over