chr1-171784089-A-G

Variant names:

• chr1-171784089-A-G
• NM_015935.5:c.503A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015935.5(METTL13):​c.503A>G​(p.Lys168Arg) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: METTL13 NM_015935.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.81
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22224939).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL13	NM_015935.5	c.503A>G	p.Lys168Arg	missense_variant	Exon 2 of 8	ENST00000361735.4	NP_057019.3
METTL13	NM_014955.3	c.245A>G	p.Lys82Arg	missense_variant	Exon 2 of 8		NP_055770.1
METTL13	NM_001007239.2	c.453+50A>G		intron_variant	Intron 2 of 7		NP_001007240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METTL13	ENST00000361735.4	c.503A>G	p.Lys168Arg	missense_variant	Exon 2 of 8	1	NM_015935.5	ENSP00000354920.3
METTL13	ENST00000367737.9	c.453+50A>G		intron_variant	Intron 2 of 7	1		ENSP00000356711.5
METTL13	ENST00000362019.7	c.245A>G	p.Lys82Arg	missense_variant	Exon 2 of 8	2		ENSP00000355393.3
METTL13	ENST00000485629.1	n.565+50A>G		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.503A>G (p.K168R) alteration is located in exon 2 (coding exon 2) of the METTL13 gene. This alteration results from a A to G substitution at nucleotide position 503, causing the lysine (K) at amino acid position 168 to be replaced by an arginine (R). 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	0.066
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	.;T
Eigen	Benign	-0.0011
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;L
PhyloP100		5.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.81	N;N
REVEL	Benign	0.091
Sift	Benign	0.28	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.31	.;B
Vest4		0.23
MutPred		0.43		.;Loss of catalytic residue at K168 (P = 0.024);
MVP		0.40
MPC		0.18
ClinPred		0.65	D
GERP RS		5.2
Varity_R		0.089
gMVP		0.30
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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

hg19: chr1-171753229;