3-15426376-C-G

Variant summary

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

The NM_152396.4(METTL6):c.136G>C(p.Asp46His) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: METTL6 NM_152396.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87

Genes affected

METTL6 (HGNC:28343): (methyltransferase 6, tRNA N3-cytidine) Enables enzyme binding activity. Involved in tRNA methylation. [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, 0.851

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
METTL6	NM_152396.4	c.136G>C	p.Asp46His	missense_variant	2/6	ENST00000383790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
METTL6	ENST00000383790.8	c.136G>C	p.Asp46His	missense_variant	2/6	1	NM_152396.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Oct 03, 2022

The c.136G>C (p.D46H) alteration is located in exon 2 (coding exon 1) of the METTL6 gene. This alteration results from a G to C substitution at nucleotide position 136, causing the aspartic acid (D) at amino acid position 46 to be replaced by a histidine (H). 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	0.95
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;.;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	3.8	H;H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.0	D;D;D;D;.
Sift	Uncertain	0.0010	D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;.
Polyphen		1.0	D;D;D;D;.
Vest4		0.94
MutPred		0.64		Loss of ubiquitination at K43 (P = 0.0286);Loss of ubiquitination at K43 (P = 0.0286);Loss of ubiquitination at K43 (P = 0.0286);Loss of ubiquitination at K43 (P = 0.0286);Loss of ubiquitination at K43 (P = 0.0286);
MVP		0.44
MPC		0.40
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-15467883;