12-57769936-G-A

Variant names:

• chr12-57769936-G-A
• rs746979244
• NM_005371.6:c.295C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005371.6(METTL1):​c.295C>T​(p.Pro99Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P99A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: METTL1 NM_005371.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.71
• Publications: 0 publications found

Genes affected

METTL1 (HGNC:7030): (methyltransferase 1, tRNA methylguanosine) This gene is similar in sequence to the S. cerevisiae YDL201w gene. The gene product contains a conserved S-adenosylmethionine-binding motif and is inactivated by phosphorylation. Alternative splice variants encoding different protein isoforms have been described for this gene. A pseudogene has been identified on chromosome X. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005371.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METTL1	NM_005371.6	MANE Select	c.295C>T	p.Pro99Ser	missense	Exon 3 of 6	NP_005362.3	Q9UBP6-1
	METTL1	NM_023033.4		c.275-258C>T		intron	N/A	NP_075422.3	Q9UBP6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METTL1	ENST00000324871.12	TSL:1 MANE Select	c.295C>T	p.Pro99Ser	missense	Exon 3 of 6	ENSP00000314441.7	Q9UBP6-1
	METTL1	ENST00000257848.7	TSL:1	c.275-258C>T		intron	N/A	ENSP00000257848.7	Q9UBP6-2
	METTL1	ENST00000927433.1		c.295C>T	p.Pro99Ser	missense	Exon 3 of 5	ENSP00000597492.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		8.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.70		Gain of catalytic residue at S95 (P = 0.0214)
MVP		0.87
MPC		0.76
ClinPred		0.99	D
GERP RS		4.9
PromoterAI		-0.00020	Neutral
Varity_R		0.58
gMVP		0.89
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs746979244; hg19: chr12-58163719;