NM_000254.3:c.2677-335A>C

Variant names:

• chr1-236884786-A-C
• rs10925260
• NM_000254.3:c.2677-335A>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.2677-335A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 150,646 control chromosomes in the GnomAD database, including 23,795 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 0.56 (23795 hom., cov: 31)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• Publications: 5 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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.2677-335A>C		intron_variant	Intron 25 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.2677-335A>C		intron_variant	Intron 25 of 32	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.1339-335A>C		intron_variant	Intron 12 of 19	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.560 AC: 84312 AN: 150528 Hom.: 23768 Cov.: 31

Gnomad AFR AF: 0.467

Gnomad AMI AF: 0.756

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.613

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.598

Gnomad OTH AF: 0.533

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

GnomAD4 genome AF: 0.560 AC: 84380 AN: 150646 Hom.: 23795 Cov.: 31 AF XY: 0.564 AC XY: 41467 AN XY: 73580

African (AFR) AF: 0.466 AC: 19262 AN: 41294

American (AMR) AF: 0.591 AC: 8990 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1702 AN: 3432

East Asian (EAS) AF: 0.558 AC: 2870 AN: 5144

South Asian (SAS) AF: 0.613 AC: 2947 AN: 4806

European-Finnish (FIN) AF: 0.629 AC: 6560 AN: 10426

Middle Eastern (MID) AF: 0.493 AC: 141 AN: 286

European-Non Finnish (NFE) AF: 0.598 AC: 40097 AN: 67040

Other (OTH) AF: 0.537 AC: 1123 AN: 2090

Alfa AF: 0.187 Hom.: 548

Bravo AF: 0.548

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.38
DANN	Benign	0.75
PhyloP100		-1.1
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: rs10925260; hg19: chr1-237048086;