rs1266164

Variant names:

• chr1-236887651-C-T
• rs1266164
• NM_000254.3:c.2851+1284C>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.2851+1284C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 152,206 control chromosomes in the GnomAD database, including 7,103 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 0.28 (7103 hom., cov: 34)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.24
• Publications: 10 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.2851+1284C>T		intron_variant	Intron 27 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.2851+1284C>T		intron_variant	Intron 27 of 32	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.1513+1284C>T		intron_variant	Intron 14 of 19	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41902 AN: 152088 Hom.: 7109 Cov.: 34

Gnomad AFR AF: 0.0820

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.314

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

GnomAD4 genome AF: 0.275 AC: 41890 AN: 152206 Hom.: 7103 Cov.: 34 AF XY: 0.274 AC XY: 20411 AN XY: 74398

African (AFR) AF: 0.0817 AC: 3397 AN: 41562

American (AMR) AF: 0.322 AC: 4915 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 1616 AN: 3468

East Asian (EAS) AF: 0.183 AC: 946 AN: 5160

South Asian (SAS) AF: 0.274 AC: 1322 AN: 4830

European-Finnish (FIN) AF: 0.348 AC: 3681 AN: 10584

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.369 AC: 25067 AN: 67998

Other (OTH) AF: 0.310 AC: 657 AN: 2116

Alfa AF: 0.346 Hom.: 4575

Bravo AF: 0.264

Asia WGS AF: 0.228 AC: 796 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.70
DANN	Benign	0.80
PhyloP100		-2.2
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: rs1266164; hg19: chr1-237050951;