1-236849589-A-G

Variant names:

• chr1-236849589-A-G
• rs12563688
• NM_000254.3:c.1516-755A>G

Variant summary

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

The NM_000254.3(MTR):​c.1516-755A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 151,954 control chromosomes in the GnomAD database, including 10,464 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 0.36 (10464 hom., cov: 31)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00300
• Publications: 2 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, ClinGen, Labcorp Genetics (formerly Invitae), 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 (EAS) allele frequency at 95% confidence interval = 0.417 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	NM_000254.3	MANE Select	c.1516-755A>G		intron	N/A	NP_000245.2
	MTR	NM_001291939.1		c.1516-755A>G		intron	N/A	NP_001278868.1
	MTR	NM_001410942.1		c.1516-755A>G		intron	N/A	NP_001397871.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	ENST00000366577.10	TSL:1 MANE Select	c.1516-755A>G		intron	N/A	ENSP00000355536.5
	MTR	ENST00000535889.6	TSL:1	c.1516-755A>G		intron	N/A	ENSP00000441845.1
	MTR	ENST00000366576.3	TSL:1	c.178-755A>G		intron	N/A	ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54310 AN: 151836 Hom.: 10456 Cov.: 31

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.360

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

GnomAD4 genome AF: 0.358 AC: 54354 AN: 151954 Hom.: 10464 Cov.: 31 AF XY: 0.359 AC XY: 26662 AN XY: 74258

African (AFR) AF: 0.216 AC: 8958 AN: 41470

American (AMR) AF: 0.413 AC: 6313 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1117 AN: 3468

East Asian (EAS) AF: 0.432 AC: 2223 AN: 5142

South Asian (SAS) AF: 0.297 AC: 1427 AN: 4800

European-Finnish (FIN) AF: 0.449 AC: 4741 AN: 10548

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

European-Non Finnish (NFE) AF: 0.415 AC: 28205 AN: 67930

Other (OTH) AF: 0.356 AC: 750 AN: 2108

Alfa AF: 0.383 Hom.: 1455

Bravo AF: 0.353

Asia WGS AF: 0.358 AC: 1244 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	4.7
DANN	Benign	0.44
PhyloP100		0.0030
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: rs12563688; hg19: chr1-237012889;