1-171783873-C-A

Variant names:

• chr1-171783873-C-A
• NM_015935.5:c.287C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015935.5(METTL13):​c.287C>A​(p.Pro96His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 5.71
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL13	NM_015935.5	c.287C>A	p.Pro96His	missense_variant	Exon 2 of 8	ENST00000361735.4	NP_057019.3
METTL13	NM_014955.3	c.29C>A	p.Pro10His	missense_variant	Exon 2 of 8		NP_055770.1
METTL13	NM_001007239.2	c.287C>A	p.Pro96His	missense_variant	Exon 2 of 8		NP_001007240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METTL13	ENST00000361735.4	c.287C>A	p.Pro96His	missense_variant	Exon 2 of 8	1	NM_015935.5	ENSP00000354920.3
METTL13	ENST00000367737.9	c.287C>A	p.Pro96His	missense_variant	Exon 2 of 8	1		ENSP00000356711.5
METTL13	ENST00000362019.7	c.29C>A	p.Pro10His	missense_variant	Exon 2 of 8	2		ENSP00000355393.3
METTL13	ENST00000485629.1	n.399C>A		non_coding_transcript_exon_variant	Exon 3 of 4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.287C>A (p.P96H) alteration is located in exon 2 (coding exon 2) of the METTL13 gene. This alteration results from a C to A substitution at nucleotide position 287, causing the proline (P) at amino acid position 96 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	Benign	0.21
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;.;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.9	.;M;M
PhyloP100		5.7
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-7.3	D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.98, 1.0	.;D;D
Vest4		0.75
MutPred		0.44		.;Gain of MoRF binding (P = 0.0652);Gain of MoRF binding (P = 0.0652);
MVP		0.82
MPC		0.87
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.88
gMVP		0.49
Mutation Taster		=26/74	disease causing

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

hg19: chr1-171753013;