1-236895062-C-T

Variant names:

• chr1-236895062-C-T
• rs12070633
• NM_000254.3:c.3406-296C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000254.3(MTR):​c.3406-296C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 427,730 control chromosomes in the GnomAD database, including 73,462 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24250 hom., cov: 31)
  • Exomes 𝑓: 0.59 (49212 hom.)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.480
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-236895062-C-T is Benign according to our data. Variant chr1-236895062-C-T is described in ClinVar as Benign. ClinVar VariationId is 1267985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.3406-296C>T		intron_variant	Intron 30 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.3406-296C>T		intron_variant	Intron 30 of 32	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.2068-296C>T		intron_variant	Intron 17 of 19	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.560 AC: 84970 AN: 151740 Hom.: 24223 Cov.: 31

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.762

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.610

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.528

GnomAD4 exome AF: 0.593 AC: 163678 AN: 275874 Hom.: 49212 Cov.: 2 AF XY: 0.596 AC XY: 87751 AN XY: 147316

African (AFR) AF: 0.456 AC: 3806 AN: 8340

American (AMR) AF: 0.616 AC: 7981 AN: 12958

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 3901 AN: 7922

East Asian (EAS) AF: 0.585 AC: 8689 AN: 14848

South Asian (SAS) AF: 0.621 AC: 25039 AN: 40328

European-Finnish (FIN) AF: 0.635 AC: 8256 AN: 12998

Middle Eastern (MID) AF: 0.537 AC: 617 AN: 1150

European-Non Finnish (NFE) AF: 0.596 AC: 96682 AN: 162194

Other (OTH) AF: 0.575 AC: 8707 AN: 15136

GnomAD4 genome AF: 0.560 AC: 85038 AN: 151856 Hom.: 24250 Cov.: 31 AF XY: 0.563 AC XY: 41809 AN XY: 74216

African (AFR) AF: 0.461 AC: 19086 AN: 41404

American (AMR) AF: 0.583 AC: 8911 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1732 AN: 3464

East Asian (EAS) AF: 0.551 AC: 2829 AN: 5130

South Asian (SAS) AF: 0.610 AC: 2929 AN: 4804

European-Finnish (FIN) AF: 0.636 AC: 6696 AN: 10526

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.602 AC: 40894 AN: 67942

Other (OTH) AF: 0.532 AC: 1123 AN: 2110

Alfa AF: 0.581 Hom.: 3220

Bravo AF: 0.551

Asia WGS AF: 0.575 AC: 1998 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.14
DANN	Benign	0.68
PhyloP100		-0.48
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: rs12070633; hg19: chr1-237058362;