Variant 18-2554671-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_022840.5(METTL4):c.827A>G(p.Asn276Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000488 in 1,601,312 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 4 hom. )

Consequence

METTL4
NM_022840.5 missense, splice_region

Scores

Splicing: ADA: 0.0003994

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.11

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:

METTL4 (HGNC:):

METTL4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01065594).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
METTL4	NM_022840.5 linkuse as main transcript	c.827A>G	p.Asn276Ser	missense_variant, splice_region_variant	4/9	ENST00000574538.2	NP_073751.3	Q8N3J2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
METTL4	ENST00000574538.2 linkuse as main transcript	c.827A>G	p.Asn276Ser	missense_variant, splice_region_variant	4/9	1	NM_022840.5	ENSP00000458290.1	Q8N3J2
METTL4	ENST00000573134.1 linkuse as main transcript	n.1224A>G		non_coding_transcript_exon_variant	3/7	1
METTL4	ENST00000319888.10 linkuse as main transcript	c.827A>G	p.Asn276Ser	missense_variant, splice_region_variant	4/8	5		ENSP00000320349.6	J3KNJ7
METTL4	ENST00000576251.5 linkuse as main transcript	c.20A>G	p.Asn7Ser	missense_variant, splice_region_variant	1/4	2		ENSP00000460774.1	I3L3W2

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000452

AC:

108

AN:

238852

Hom.:

AF XY:

0.000368

AC XY:

AN XY:

130464

show subpopulations

Gnomad AFR exome

AF:

0.0000672

Gnomad AMR exome

AF:

0.000658

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000340

Gnomad FIN exome

AF:

0.000650

Gnomad NFE exome

AF:

0.000619

Gnomad OTH exome

AF:

0.000689

GnomAD4 exome

AF:

0.000484

AC:

702

AN:

1449070

Hom.:

Cov.:

AF XY:

0.000500

AC XY:

361

AN XY:

721564

show subpopulations

Gnomad4 AFR exome

AF:

0.0000313

Gnomad4 AMR exome

AF:

0.000878

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000352

Gnomad4 FIN exome

AF:

0.000680

Gnomad4 NFE exome

AF:

0.000545

Gnomad4 OTH exome

AF:

0.000351

GnomAD4 genome

AF:

0.000519

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000540

Hom.:

Bravo

AF:

0.000540

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000941

AC:

ExAC

AF:

0.000495

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.827A>G (p.N276S) alteration is located in exon 4 (coding exon 3) of the METTL4 gene. This alteration results from a A to G substitution at nucleotide position 827, causing the asparagine (N) at amino acid position 276 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0050

.;T

Eigen

Benign

0.078

Eigen_PC

Benign

0.079

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.0065

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.7

.;M

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.9

N;.

REVEL

Benign

0.068

Sift

Benign

0.059

T;.

Sift4G

Uncertain

0.039

D;T

Polyphen

0.93

.;P

Vest4

0.18

MVP

0.71

MPC

0.079

ClinPred

0.049

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.049

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00040

dbscSNV1_RF

Benign

0.0080

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over