1-171782050-C-A

Variant names:

• chr1-171782050-C-A
• rs368751643
• NM_015935.5:c.83C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015935.5(METTL13):​c.83C>A​(p.Ala28Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: METTL13 NM_015935.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.29
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3689062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL13	NM_015935.5	c.83C>A	p.Ala28Asp	missense_variant	Exon 1 of 8	ENST00000361735.4	NP_057019.3
METTL13	NM_001007239.2	c.83C>A	p.Ala28Asp	missense_variant	Exon 1 of 8		NP_001007240.1
METTL13	NM_014955.3	c.-106+255C>A		intron_variant	Intron 1 of 7		NP_055770.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METTL13	ENST00000361735.4	c.83C>A	p.Ala28Asp	missense_variant	Exon 1 of 8	1	NM_015935.5	ENSP00000354920.3
METTL13	ENST00000367737.9	c.83C>A	p.Ala28Asp	missense_variant	Exon 1 of 8	1		ENSP00000356711.5
METTL13	ENST00000485629.1	n.195C>A		non_coding_transcript_exon_variant	Exon 2 of 4	5
METTL13	ENST00000362019.7	c.-106+255C>A		intron_variant	Intron 1 of 7	2		ENSP00000355393.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.83C>A (p.A28D) alteration is located in exon 1 (coding exon 1) of the METTL13 gene. This alteration results from a C to A substitution at nucleotide position 83, causing the alanine (A) at amino acid position 28 to be replaced by an aspartic acid (D). 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	Uncertain	0.36
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.6	M;M
PhyloP100		5.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.74	P;P
Vest4		0.47
MutPred		0.44		Gain of ubiquitination at K26 (P = 0.041);Gain of ubiquitination at K26 (P = 0.041);
MVP		0.81
MPC		0.60
ClinPred		0.99	D
GERP RS		4.6
PromoterAI		0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.63
gMVP		0.77
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs368751643; hg19: chr1-171751190;