12-57768956-A-G

Position:

• chr12-57768956-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005371.6(METTL1):​c.*40T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,581,434 control chromosomes in the GnomAD database, including 103,017 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 0.34 (9194 hom., cov: 33)
  • Exomes 𝑓: 0.35 (93823 hom.)
• Consequence: METTL1 NM_005371.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.77

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]

CYP27B1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
METTL1	NM_005371.6	c.*40T>C		3_prime_UTR_variant	6/6	ENST00000324871.12	NP_005362.3
METTL1	NM_023033.4	c.*218T>C		3_prime_UTR_variant	5/5		NP_075422.3
METTL1	XM_005268873.3	c.*40T>C		3_prime_UTR_variant	7/7		XP_005268930.1
METTL1	XM_047428854.1	c.*40T>C		3_prime_UTR_variant	5/5		XP_047284810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
METTL1	ENST00000324871	c.*40T>C		3_prime_UTR_variant	6/6	1	NM_005371.6	ENSP00000314441.7
METTL1	ENST00000257848	c.*218T>C		3_prime_UTR_variant	5/5	1		ENSP00000257848.7
CYP27B1	ENST00000546609.1	c.29T>C	p.Ile10Thr	missense_variant	1/4	5
METTL1	ENST00000547653	c.*218T>C		3_prime_UTR_variant	3/3	3		ENSP00000447838.1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51388 AN: 151942 Hom.: 9165 Cov.: 33

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.656

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.288

GnomAD3 exomes AF: 0.384 AC: 93998 AN: 245090 Hom.: 19687 AF XY: 0.390 AC XY: 51534 AN XY: 132258

Gnomad AFR exome AF: 0.319

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.291

Gnomad EAS exome AF: 0.634

Gnomad SAS exome AF: 0.556

Gnomad FIN exome AF: 0.365

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.331

GnomAD4 exome AF: 0.352 AC: 502796 AN: 1429374 Hom.: 93823 Cov.: 33 AF XY: 0.357 AC XY: 251672 AN XY: 704614

Gnomad4 AFR exome AF: 0.310

Gnomad4 AMR exome AF: 0.353

Gnomad4 ASJ exome AF: 0.301

Gnomad4 EAS exome AF: 0.700

Gnomad4 SAS exome AF: 0.545

Gnomad4 FIN exome AF: 0.358

Gnomad4 NFE exome AF: 0.327

Gnomad4 OTH exome AF: 0.348

GnomAD4 genome AF: 0.338 AC: 51467 AN: 152060 Hom.: 9194 Cov.: 33 AF XY: 0.346 AC XY: 25734 AN XY: 74338

Gnomad4 AFR AF: 0.319

Gnomad4 AMR AF: 0.285

Gnomad4 ASJ AF: 0.298

Gnomad4 EAS AF: 0.656

Gnomad4 SAS AF: 0.559

Gnomad4 FIN AF: 0.378

Gnomad4 NFE AF: 0.320

Gnomad4 OTH AF: 0.294

Alfa AF: 0.326 Hom.: 13758

Bravo AF: 0.327

Asia WGS AF: 0.603 AC: 2093 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.9
DANN	Benign	0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs703842; hg19: chr12-58162739; COSMIC: COSV55743659; COSMIC: COSV55743659;