chr12-57769596-A-G

Variant names:

• chr12-57769596-A-G
• rs863223376
• NM_005371.6:c.542T>C

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.542T>C​(p.Leu181Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000451 in 1,551,694 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: METTL1 NM_005371.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 8.93
• 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, 0.923

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.542T>C	p.Leu181Pro	missense	Exon 4 of 6	NP_005362.3	Q9UBP6-1
	METTL1	NM_023033.4		c.357T>C	p.Ala119Ala	synonymous	Exon 3 of 5	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.542T>C	p.Leu181Pro	missense	Exon 4 of 6	ENSP00000314441.7	Q9UBP6-1
	METTL1	ENST00000257848.7	TSL:1	c.357T>C	p.Ala119Ala	synonymous	Exon 3 of 5	ENSP00000257848.7	Q9UBP6-2
	METTL1	ENST00000966255.1		c.518T>C	p.Leu173Pro	missense	Exon 4 of 6	ENSP00000636314.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000429 AC: 6 AN: 1399468 Hom.: 0 Cov.: 32 AF XY: 0.00000436 AC XY: 3 AN XY: 687662

African (AFR) AF: 0.00 AC: 0 AN: 31998

American (AMR) AF: 0.00 AC: 0 AN: 39024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21798

East Asian (EAS) AF: 0.00 AC: 0 AN: 39110

South Asian (SAS) AF: 0.00 AC: 0 AN: 75780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5458

European-Non Finnish (NFE) AF: 0.00000557 AC: 6 AN: 1077884

Other (OTH) AF: 0.00 AC: 0 AN: 57622

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74378

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Abnormality of neuronal migration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.22	D
PhyloP100		8.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.92
MPC		0.99
ClinPred		0.99	D
GERP RS		5.7
PromoterAI		0.010	Neutral
Varity_R		0.98
gMVP		0.97
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs863223376; hg19: chr12-58163379;