12-57771302-C-T

Variant names:

• chr12-57771302-C-T
• rs10877013
• NM_005371.6:c.111-45G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005371.6(METTL1):​c.111-45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,476,274 control chromosomes in the GnomAD database, including 101,673 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (8550 hom., cov: 32)
  • Exomes 𝑓: 0.38 (93123 hom.)
• Consequence: METTL1 NM_005371.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.295
• Publications: 62 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]

EEF1AKMT3 (HGNC:24936): (EEF1A lysine methyltransferase 3) Enables heat shock protein binding activity and protein-lysine N-methyltransferase activity. Involved in peptidyl-lysine methylation. Located in several cellular components, including centrosome; chromosome; and nucleoplasm. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
METTL1	NM_005371.6	c.111-45G>A		intron_variant	Intron 1 of 5	ENST00000324871.12	NP_005362.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
METTL1	ENST00000324871.12	c.111-45G>A		intron_variant	Intron 1 of 5	1	NM_005371.6	ENSP00000314441.7

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49191 AN: 150026 Hom.: 8524 Cov.: 32

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.673

Gnomad SAS AF: 0.566

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.277

GnomAD2 exomes AF: 0.381 AC: 90365 AN: 237072 AF XY: 0.388

Gnomad AFR exome AF: 0.276

Gnomad AMR exome AF: 0.360

Gnomad ASJ exome AF: 0.278

Gnomad EAS exome AF: 0.651

Gnomad FIN exome AF: 0.365

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.328

GnomAD4 exome AF: 0.378 AC: 501516 AN: 1326124 Hom.: 93123 Cov.: 28 AF XY: 0.384 AC XY: 252902 AN XY: 659168

African (AFR) AF: 0.292 AC: 8606 AN: 29430

American (AMR) AF: 0.370 AC: 14998 AN: 40488

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 7185 AN: 21724

East Asian (EAS) AF: 0.730 AC: 28137 AN: 38560

South Asian (SAS) AF: 0.550 AC: 45444 AN: 82616

European-Finnish (FIN) AF: 0.407 AC: 18796 AN: 46228

Middle Eastern (MID) AF: 0.237 AC: 1199 AN: 5054

European-Non Finnish (NFE) AF: 0.354 AC: 356779 AN: 1008960

Other (OTH) AF: 0.384 AC: 20372 AN: 53064

GnomAD4 genome AF: 0.328 AC: 49266 AN: 150150 Hom.: 8550 Cov.: 32 AF XY: 0.336 AC XY: 24662 AN XY: 73348

African (AFR) AF: 0.276 AC: 11327 AN: 41054

American (AMR) AF: 0.283 AC: 4266 AN: 15100

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 988 AN: 3434

East Asian (EAS) AF: 0.673 AC: 3441 AN: 5116

South Asian (SAS) AF: 0.567 AC: 2687 AN: 4740

European-Finnish (FIN) AF: 0.391 AC: 3969 AN: 10154

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.321 AC: 21598 AN: 67272

Other (OTH) AF: 0.284 AC: 592 AN: 2088

Alfa AF: 0.311 Hom.: 14003

Bravo AF: 0.312

Asia WGS AF: 0.602 AC: 2091 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	9.8
DANN	Benign	0.54
PhyloP100		-0.29
PromoterAI		0.0081	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs10877013; hg19: chr12-58165085;