12-57768956-A-G

Variant names:

• chr12-57768956-A-G
• rs703842
• NM_005371.6:c.*40T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 207 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]

CYP27B1 (HGNC:2606): (cytochrome P450 family 27 subfamily B member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. The protein encoded by this gene localizes to the inner mitochondrial membrane where it hydroxylates 25-hydroxyvitamin D3 at the 1alpha position. This reaction synthesizes 1alpha,25-dihydroxyvitamin D3, the active form of vitamin D3, which binds to the vitamin D receptor and regulates calcium metabolism. Thus this enzyme regulates the level of biologically active vitamin D and plays an important role in calcium homeostasis. Mutations in this gene can result in vitamin D-dependent rickets type I. [provided by RefSeq, Jul 2008]

CYP27B1 Gene-Disease associations (from GenCC):

• vitamin D-dependent rickets, type 1A

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• vitamin D-dependent rickets, type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

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.*40T>C		3_prime_UTR	Exon 6 of 6	NP_005362.3	Q9UBP6-1
	METTL1	NM_023033.4		c.*218T>C		3_prime_UTR	Exon 5 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.*40T>C		3_prime_UTR	Exon 6 of 6	ENSP00000314441.7	Q9UBP6-1
	METTL1	ENST00000257848.7	TSL:1	c.*218T>C		3_prime_UTR	Exon 5 of 5	ENSP00000257848.7	Q9UBP6-2
	METTL1	ENST00000966255.1		c.*40T>C		3_prime_UTR	Exon 6 of 6	ENSP00000636314.1

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

GnomAD2 exomes AF: 0.384 AC: 93998 AN: 245090 AF XY: 0.390

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 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

African (AFR) AF: 0.310 AC: 10206 AN: 32952

American (AMR) AF: 0.353 AC: 15558 AN: 44026

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 7595 AN: 25238

East Asian (EAS) AF: 0.700 AC: 27242 AN: 38930

South Asian (SAS) AF: 0.545 AC: 46141 AN: 84692

European-Finnish (FIN) AF: 0.358 AC: 18843 AN: 52702

Middle Eastern (MID) AF: 0.233 AC: 949 AN: 4066

European-Non Finnish (NFE) AF: 0.327 AC: 355825 AN: 1088012

Other (OTH) AF: 0.348 AC: 20437 AN: 58756

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

African (AFR) AF: 0.319 AC: 13219 AN: 41456

American (AMR) AF: 0.285 AC: 4362 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1035 AN: 3472

East Asian (EAS) AF: 0.656 AC: 3389 AN: 5168

South Asian (SAS) AF: 0.559 AC: 2691 AN: 4818

European-Finnish (FIN) AF: 0.378 AC: 4002 AN: 10580

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.320 AC: 21748 AN: 67968

Other (OTH) AF: 0.294 AC: 621 AN: 2112

Alfa AF: 0.333 Hom.: 32539

Bravo AF: 0.327

Asia WGS AF: 0.603 AC: 2093 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	9.9
DANN	Benign	0.83
PhyloP100		1.8
PromoterAI		-0.0058	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: rs703842; hg19: chr12-58162739; COSMIC: COSV55743659; COSMIC: COSV55743659;