chr4-118697240-G-A

Position:

• chr4-118697240-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020961.4(METTL14):​c.562G>A​(p.Val188Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: METTL14 NM_020961.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.07

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
METTL14	NM_020961.4	c.562G>A	p.Val188Met	missense_variant	7/11	ENST00000388822.10
METTL14	XM_047416029.1	c.562G>A	p.Val188Met	missense_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
METTL14	ENST00000388822.10	c.562G>A	p.Val188Met	missense_variant	7/11	1	NM_020961.4	P1
METTL14	ENST00000506780.2	c.31G>A	p.Val11Met	missense_variant	1/4	5
METTL14	ENST00000502564.2	n.317G>A		non_coding_transcript_exon_variant	4/4	5
METTL14	ENST00000628452.2	c.*293G>A		3_prime_UTR_variant, NMD_transcript_variant	7/11	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.562G>A (p.V188M) alteration is located in exon 7 (coding exon 7) of the METTL14 gene. This alteration results from a G to A substitution at nucleotide position 562, causing the valine (V) at amino acid position 188 to be replaced by a methionine (M). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.70		Gain of glycosylation at T183 (P = 0.0139);
MVP		0.77
MPC		1.7
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.85

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

Other links and lift over

dbSNP: rs1411588847; hg19: chr4-119618395;