1-236863924-T-C

Variant names:

• chr1-236863924-T-C
• rs2297967
• NM_000254.3:c.2405+370T>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.2405+370T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.72 in 151,878 control chromosomes in the GnomAD database, including 40,597 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 0.72 (40597 hom., cov: 29)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.460
• Publications: 0 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.895 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.2405+370T>C		intron	N/A	NP_000245.2
	MTR	NM_001291939.1		c.2252+370T>C		intron	N/A	NP_001278868.1
	MTR	NM_001410942.1		c.2405+370T>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.2405+370T>C		intron	N/A	ENSP00000355536.5
	MTR	ENST00000535889.6	TSL:1	c.2252+370T>C		intron	N/A	ENSP00000441845.1
	MTR	ENST00000366576.3	TSL:1	c.1067+370T>C		intron	N/A	ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109288 AN: 151762 Hom.: 40547 Cov.: 29

Gnomad AFR AF: 0.903

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.677

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.813

Gnomad SAS AF: 0.727

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.682

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

GnomAD4 genome AF: 0.720 AC: 109400 AN: 151878 Hom.: 40597 Cov.: 29 AF XY: 0.721 AC XY: 53492 AN XY: 74194

African (AFR) AF: 0.903 AC: 37407 AN: 41434

American (AMR) AF: 0.677 AC: 10335 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1858 AN: 3470

East Asian (EAS) AF: 0.813 AC: 4178 AN: 5136

South Asian (SAS) AF: 0.726 AC: 3480 AN: 4794

European-Finnish (FIN) AF: 0.652 AC: 6877 AN: 10554

Middle Eastern (MID) AF: 0.630 AC: 184 AN: 292

European-Non Finnish (NFE) AF: 0.632 AC: 42906 AN: 67912

Other (OTH) AF: 0.686 AC: 1444 AN: 2106

Alfa AF: 0.651 Hom.: 14125

Bravo AF: 0.731

Asia WGS AF: 0.771 AC: 2679 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.9
DANN	Benign	0.60
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2297967; hg19: chr1-237027224;