1-171784049-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_015935.5(METTL13):c.463C>T(p.Arg155Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: METTL13 NM_015935.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.38

Genes affected

METTL13 (HGNC:24248): (methyltransferase 13, eEF1A N-terminus and K55) Predicted to enable methyltransferase activity. Involved in negative regulation of cell cycle G1/S phase transition and negative regulation of transcription by RNA polymerase II. Predicted to be located in mitochondrion and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
METTL13	NM_015935.5	c.463C>T	p.Arg155Cys	missense_variant	2/8	ENST00000361735.4
METTL13	NM_014955.3	c.205C>T	p.Arg69Cys	missense_variant	2/8
METTL13	NM_001007239.2	c.453+10C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
METTL13	ENST00000361735.4	c.463C>T	p.Arg155Cys	missense_variant	2/8	1	NM_015935.5	P1
METTL13	ENST00000367737.9	c.453+10C>T		intron_variant		1
METTL13	ENST00000362019.7	c.205C>T	p.Arg69Cys	missense_variant	2/8	2
METTL13	ENST00000485629.1	n.565+10C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461870 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

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: 0.0000374

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

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

Dec 01, 2022

The c.463C>T (p.R155C) alteration is located in exon 2 (coding exon 2) of the METTL13 gene. This alteration results from a C to T substitution at nucleotide position 463, causing the arginine (R) at amino acid position 155 to be replaced by a cysteine (C). 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	0.28
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.51	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.2	D;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.97
MVP		0.77
MPC		0.97
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.93
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs373455201; hg19: chr1-171753189;