chr11-28290249-G-A

Position:

• chr11-28290249-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001113528.2(METTL15):​c.451G>A​(p.Ala151Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: METTL15 NM_001113528.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.439

Genes affected

METTL15 (HGNC:26606): (methyltransferase 15, mitochondrial 12S rRNA N4-cytidine) Predicted to enable rRNA (cytosine-N4-)-methyltransferase activity. Predicted to be involved in rRNA base methylation. Predicted to be located in mitochondrial matrix. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.033786535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
METTL15	NM_001113528.2	c.451G>A	p.Ala151Thr	missense_variant	5/7	ENST00000407364.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
METTL15	ENST00000407364.8	c.451G>A	p.Ala151Thr	missense_variant	5/7	5	NM_001113528.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460862 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726704

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

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

Jul 13, 2021

The c.451G>A (p.A151T) alteration is located in exon 5 (coding exon 3) of the METTL15 gene. This alteration results from a G to A substitution at nucleotide position 451, causing the alanine (A) at amino acid position 151 to be replaced by a threonine (T). 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	0.071
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Benign	0.72
DEOGEN2	Benign	0.020	.;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.68
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.32	T;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.034	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.73	N;N;N
MutationTaster	Benign	0.61	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.79	N;N;N
REVEL	Benign	0.020
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.76	T;T;T
Polyphen		0.11	B;B;B
Vest4		0.12
MutPred		0.32		Gain of phosphorylation at A151 (P = 0.0833);Gain of phosphorylation at A151 (P = 0.0833);Gain of phosphorylation at A151 (P = 0.0833);
MVP		0.040
MPC		0.075
ClinPred		0.20	T
GERP RS		0.77
Varity_R		0.070
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs1856457368; hg19: chr11-28311796;