1-236808698-C-T

Variant names:

• chr1-236808698-C-T
• rs7526063
• NM_000254.3:c.340-6C>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.340-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 1,613,758 control chromosomes in the GnomAD database, including 1,421 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (385 hom., cov: 32)
  • Exomes 𝑓: 0.026 (1036 hom.)
• Consequence: MTR NM_000254.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002343
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.58
• Publications: 14 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=-0.82).
• BP6: Variant 1-236808698-C-T is Benign according to our data. Variant chr1-236808698-C-T is described in ClinVar as Benign. ClinVar VariationId is 138287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.340-6C>T		splice_region_variant, intron_variant	Intron 3 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.340-6C>T		splice_region_variant, intron_variant	Intron 3 of 32	1	NM_000254.3	ENSP00000355536.5

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8357 AN: 152160 Hom.: 383 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0404

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.0539

Gnomad SAS AF: 0.0900

Gnomad FIN AF: 0.0165

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0507

GnomAD2 exomes AF: 0.0378 AC: 9494 AN: 251404 AF XY: 0.0377

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0315

Gnomad ASJ exome AF: 0.00913

Gnomad EAS exome AF: 0.0521

Gnomad FIN exome AF: 0.0169

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0342

GnomAD4 exome AF: 0.0265 AC: 38658 AN: 1461480 Hom.: 1036 Cov.: 31 AF XY: 0.0279 AC XY: 20257 AN XY: 727068

African (AFR) AF: 0.132 AC: 4402 AN: 33446

American (AMR) AF: 0.0330 AC: 1476 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 264 AN: 26134

East Asian (EAS) AF: 0.0632 AC: 2509 AN: 39694

South Asian (SAS) AF: 0.0770 AC: 6642 AN: 86238

European-Finnish (FIN) AF: 0.0168 AC: 900 AN: 53416

Middle Eastern (MID) AF: 0.0506 AC: 292 AN: 5768

European-Non Finnish (NFE) AF: 0.0182 AC: 20239 AN: 1111692

Other (OTH) AF: 0.0320 AC: 1934 AN: 60380

GnomAD4 genome AF: 0.0550 AC: 8376 AN: 152278 Hom.: 385 Cov.: 32 AF XY: 0.0553 AC XY: 4121 AN XY: 74468

African (AFR) AF: 0.127 AC: 5259 AN: 41532

American (AMR) AF: 0.0402 AC: 615 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.0540 AC: 280 AN: 5184

South Asian (SAS) AF: 0.0896 AC: 433 AN: 4832

European-Finnish (FIN) AF: 0.0165 AC: 175 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0211 AC: 1437 AN: 68032

Other (OTH) AF: 0.0506 AC: 107 AN: 2114

Alfa AF: 0.0321 Hom.: 289

Bravo AF: 0.0591

Asia WGS AF: 0.0810 AC: 284 AN: 3478

EpiCase AF: 0.0236

EpiControl AF: 0.0216

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Oct 03, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Disorders of Intracellular Cobalamin Metabolism Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Methylcobalamin deficiency type cblG Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

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	-0.82
CADD	Benign	6.1
DANN	Benign	0.54
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=70/30	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.074
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: rs7526063; hg19: chr1-236971998; COSMIC: COSV63967404;