1-236846557-C-T

Variant names:

• chr1-236846557-C-T
• rs3754255
• NM_000254.3:c.1516-3787C>T

Variant summary

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

The NM_000254.3(MTR):​c.1516-3787C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 151,930 control chromosomes in the GnomAD database, including 14,688 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 0.44 (14688 hom., cov: 33)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.55
• 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, 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.474 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.1516-3787C>T		intron	N/A	NP_000245.2	Q99707-1
	MTR	NM_001291939.1		c.1516-3787C>T		intron	N/A	NP_001278868.1	Q99707-2
	MTR	NM_001410942.1		c.1516-3787C>T		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.1516-3787C>T		intron	N/A	ENSP00000355536.5	Q99707-1
	MTR	ENST00000535889.6	TSL:1	c.1516-3787C>T		intron	N/A	ENSP00000441845.1	Q99707-2
	MTR	ENST00000366576.3	TSL:1	c.178-3787C>T		intron	N/A	ENSP00000355535.3	B1ANE3

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66331 AN: 151812 Hom.: 14671 Cov.: 33

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.461

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.488

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.434

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

GnomAD4 genome AF: 0.437 AC: 66398 AN: 151930 Hom.: 14688 Cov.: 33 AF XY: 0.437 AC XY: 32467 AN XY: 74260

African (AFR) AF: 0.434 AC: 17956 AN: 41382

American (AMR) AF: 0.461 AC: 7048 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1141 AN: 3472

East Asian (EAS) AF: 0.490 AC: 2527 AN: 5160

South Asian (SAS) AF: 0.387 AC: 1864 AN: 4812

European-Finnish (FIN) AF: 0.464 AC: 4889 AN: 10548

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.433 AC: 29400 AN: 67946

Other (OTH) AF: 0.430 AC: 908 AN: 2114

Alfa AF: 0.313 Hom.: 819

Bravo AF: 0.441

Asia WGS AF: 0.442 AC: 1535 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.081
DANN	Benign	0.43
PhyloP100		-2.5
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: rs3754255; hg19: chr1-237009857;