Genetic Variant ENST00000573134.1:n.4174G>T (chr18-2538546-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000573134.1(METTL4):n.4174G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 154,356 control chromosomes in the GnomAD database, including 5,393 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 0.26 ( 5347 hom., cov: 32)

Exomes 𝑓: 0.18 ( 46 hom. )

Consequence

METTL4
ENST00000573134.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.123

Publications

8 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=-0.87).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL4	NM_022840.5 link	c.*454G>T		3_prime_UTR_variant	Exon 9 of 9	ENST00000574538.2	NP_073751.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
METTL4	ENST00000573134.1 link	n.4174G>T	non_coding_transcript_exon_variant	Exon 7 of 7	1
METTL4	ENST00000574538.2 link	c.*454G>T	3_prime_UTR_variant	Exon 9 of 9	1	NM_022840.5	ENSP00000458290.1
METTL4	ENST00000319888.10 link	c.*521G>T	3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000320349.6
METTL4	ENST00000576251.5 link	c.*591G>T	3_prime_UTR_variant	Exon 4 of 4	2		ENSP00000460774.1

Frequencies

GnomAD3 genomes

AF:

0.256

AC:

38848

AN:

151994

Hom.:

5346

Cov.:

show subpopulations

Gnomad AFR

AF:

0.349

Gnomad AMI

AF:

0.0648

Gnomad AMR

AF:

0.194

Gnomad ASJ

AF:

0.168

Gnomad EAS

AF:

0.0556

Gnomad SAS

AF:

0.154

Gnomad FIN

AF:

0.245

Gnomad MID

AF:

0.256

Gnomad NFE

AF:

0.244

Gnomad OTH

AF:

0.233

GnomAD4 exome

AF:

0.176

AC:

394

AN:

2244

Hom.:

Cov.:

AF XY:

0.164

AC XY:

201

AN XY:

1224

show subpopulations

African (AFR)

AF:

0.423

AC:

AN:

American (AMR)

AF:

0.117

AC:

AN:

290

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

AN:

East Asian (EAS)

AF:

0.0444

AC:

AN:

South Asian (SAS)

AF:

0.135

AC:

AN:

192

European-Finnish (FIN)

AF:

0.133

AC:

AN:

Middle Eastern (MID)

AF:

0.125

AC:

AN:

European-Non Finnish (NFE)

AF:

0.197

AC:

297

AN:

1504

Other (OTH)

AF:

0.138

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.256

AC:

38880

AN:

152112

Hom.:

5347

Cov.:

AF XY:

0.252

AC XY:

18732

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.349

AC:

14479

AN:

41478

American (AMR)

AF:

0.194

AC:

2955

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

585

AN:

3472

East Asian (EAS)

AF:

0.0558

AC:

289

AN:

5182

South Asian (SAS)

AF:

0.153

AC:

738

AN:

4824

European-Finnish (FIN)

AF:

0.245

AC:

2593

AN:

10592

Middle Eastern (MID)

AF:

0.276

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.244

AC:

16607

AN:

67978

Other (OTH)

AF:

0.233

AC:

494

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1434

2868

4301

5735

7169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

398

796

1194

1592

1990

<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:

0.232

Hom.:

7038

Bravo

AF:

0.253

Asia WGS

AF:

0.123

AC:

428

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

3.2

(source)

DANN

Benign

0.70

PhyloP100

-0.12

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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