Variant 4-118700595-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020961.4(METTL14):c.691A>G(p.Ile231Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000738 in 1,613,036 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

METTL14
NM_020961.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.81

Variant links:

Genes affected

METTL14 (HGNC:29330): (methyltransferase 14, N6-adenosine-methyltransferase subunit) Enables mRNA binding activity. Contributes to mRNA (2'-O-methyladenosine-N6-)-methyltransferase activity. Involved in mRNA metabolic process; negative regulation of hematopoietic progenitor cell differentiation; and positive regulation of translation. Located in nucleoplasm. Part of RNA N6-methyladenosine methyltransferase complex. [provided by Alliance of Genome Resources, Apr 2022]

METTL14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.029576957).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
METTL14	NM_020961.4 linkuse as main transcript	c.691A>G	p.Ile231Val	missense_variant	8/11	ENST00000388822.10
METTL14	XM_047416029.1 linkuse as main transcript	c.691A>G	p.Ile231Val	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
METTL14	ENST00000388822.10 linkuse as main transcript	c.691A>G	p.Ile231Val	missense_variant	8/11	1	NM_020961.4	P1
METTL14	ENST00000506780.2 linkuse as main transcript	c.160A>G	p.Ile54Val	missense_variant	2/4	5
METTL14	ENST00000628452.2 linkuse as main transcript	c.*422A>G		3_prime_UTR_variant, NMD_transcript_variant	8/11	5

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000990

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000107

AC:

AN:

251318

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1460866

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726780

show subpopulations

Gnomad4 AFR exome

AF:

0.000897

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.000329

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.000987

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000378

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000106

Hom.:

Bravo

AF:

0.000272

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000123

AC:

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

Sep 13, 2023

The c.691A>G (p.I231V) alteration is located in exon 8 (coding exon 8) of the METTL14 gene. This alteration results from a A to G substitution at nucleotide position 691, causing the isoleucine (I) at amino acid position 231 to be replaced by a valine (V). 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

0.072

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.50

DEOGEN2

Benign

0.030

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.0032

MetaRNN

Benign

0.030

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.32

MutationTaster

Benign

0.56

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.090

REVEL

Benign

0.13

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.14

MVP

0.23

MPC

0.58

ClinPred

0.078

GERP RS

1.4

Varity_R

0.046

gMVP

0.36

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

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