rs10925252

Variant names:

• chr1-236859062-T-C
• rs10925252
• NM_000254.3:c.1954-771T>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.1954-771T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 152,188 control chromosomes in the GnomAD database, including 10,199 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 (10199 hom., cov: 33)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.921
• Publications: 4 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.42 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.1954-771T>C		intron	N/A	NP_000245.2
	MTR	NM_001291939.1		c.1954-771T>C		intron	N/A	NP_001278868.1
	MTR	NM_001410942.1		c.1954-771T>C		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.1954-771T>C		intron	N/A	ENSP00000355536.5
	MTR	ENST00000535889.6	TSL:1	c.1954-771T>C		intron	N/A	ENSP00000441845.1
	MTR	ENST00000366576.3	TSL:1	c.616-771T>C		intron	N/A	ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53465 AN: 152068 Hom.: 10194 Cov.: 33

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.353

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

GnomAD4 genome AF: 0.352 AC: 53497 AN: 152188 Hom.: 10199 Cov.: 33 AF XY: 0.353 AC XY: 26268 AN XY: 74410

African (AFR) AF: 0.204 AC: 8467 AN: 41534

American (AMR) AF: 0.411 AC: 6282 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1113 AN: 3470

East Asian (EAS) AF: 0.435 AC: 2248 AN: 5166

South Asian (SAS) AF: 0.297 AC: 1434 AN: 4828

European-Finnish (FIN) AF: 0.445 AC: 4710 AN: 10580

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

European-Non Finnish (NFE) AF: 0.410 AC: 27889 AN: 67998

Other (OTH) AF: 0.349 AC: 737 AN: 2112

Alfa AF: 0.377 Hom.: 1408

Bravo AF: 0.347

Asia WGS AF: 0.357 AC: 1242 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.2
DANN	Benign	0.43
PhyloP100		0.92
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: rs10925252; hg19: chr1-237022362;