rs12060570

Variant names:

• chr1-236825769-G-C
• rs12060570
• NM_000254.3:c.927+370G>C

Variant summary

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

The NM_000254.3(MTR):​c.927+370G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 152,066 control chromosomes in the GnomAD database, including 10,083 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 0.35 (10083 hom., cov: 32)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.24
• Publications: 6 publications found

Genes affected

MTR (HGNC:7468): (5-methyltetrahydrofolate-homocysteine methyltransferase) This gene encodes the 5-methyltetrahydrofolate-homocysteine methyltransferase. This enzyme, also known as cobalamin-dependent methionine synthase, catalyzes the final step in methionine biosynthesis. Mutations in MTR have been identified as the underlying cause of methylcobalamin deficiency complementation group G. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

MTR Gene-Disease associations (from GenCC):

• methylcobalamin deficiency type cblG

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000254.3. 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
	MTR	NM_000254.3	MANE Select	c.927+370G>C		intron	N/A	NP_000245.2	Q99707-1
	MTR	NM_001291939.1		c.927+370G>C		intron	N/A	NP_001278868.1	Q99707-2
	MTR	NM_001410942.1		c.927+370G>C		intron	N/A	NP_001397871.1	A0A7P0TAJ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	ENST00000366577.10	TSL:1 MANE Select	c.927+370G>C		intron	N/A	ENSP00000355536.5	Q99707-1
	MTR	ENST00000535889.6	TSL:1	c.927+370G>C		intron	N/A	ENSP00000441845.1	Q99707-2
	MTR	ENST00000681102.1		c.927+370G>C		intron	N/A	ENSP00000505600.1	A0A7P0T9G7

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53162 AN: 151948 Hom.: 10077 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.352

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.350 AC: 53203 AN: 152066 Hom.: 10083 Cov.: 32 AF XY: 0.351 AC XY: 26103 AN XY: 74322

African (AFR) AF: 0.207 AC: 8586 AN: 41506

American (AMR) AF: 0.407 AC: 6229 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1057 AN: 3472

East Asian (EAS) AF: 0.404 AC: 2086 AN: 5166

South Asian (SAS) AF: 0.296 AC: 1425 AN: 4808

European-Finnish (FIN) AF: 0.434 AC: 4587 AN: 10564

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.410 AC: 27887 AN: 67952

Other (OTH) AF: 0.348 AC: 734 AN: 2108

Alfa AF: 0.377 Hom.: 1409

Bravo AF: 0.346

Asia WGS AF: 0.347 AC: 1205 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.11
DANN	Benign	0.52
PhyloP100		-4.2
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: rs12060570; hg19: chr1-236989069;