1-236897133-G-T

Variant names:

• chr1-236897133-G-T
• rs3820571
• NM_000254.3:c.3711+15G>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.3711+15G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.65 in 1,572,696 control chromosomes in the GnomAD database, including 336,976 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39187 hom., cov: 32)
  • Exomes 𝑓: 0.64 (297789 hom.)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.202
• Publications: 19 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=-0.9).
• BP6: Variant 1-236897133-G-T is Benign according to our data. Variant chr1-236897133-G-T is described in ClinVar as Benign. ClinVar VariationId is 138285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.87 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.3711+15G>T		intron_variant	Intron 32 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.3711+15G>T		intron_variant	Intron 32 of 32	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.2373+15G>T		intron_variant	Intron 19 of 19	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.708 AC: 107558 AN: 151950 Hom.: 39138 Cov.: 32

Gnomad AFR AF: 0.877

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.814

Gnomad SAS AF: 0.726

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.661

GnomAD2 exomes AF: 0.670 AC: 168298 AN: 251296 AF XY: 0.664

Gnomad AFR exome AF: 0.887

Gnomad AMR exome AF: 0.681

Gnomad ASJ exome AF: 0.512

Gnomad EAS exome AF: 0.808

Gnomad FIN exome AF: 0.653

Gnomad NFE exome AF: 0.618

Gnomad OTH exome AF: 0.647

GnomAD4 exome AF: 0.644 AC: 915305 AN: 1420628 Hom.: 297789 Cov.: 27 AF XY: 0.645 AC XY: 457922 AN XY: 709554

African (AFR) AF: 0.889 AC: 28979 AN: 32594

American (AMR) AF: 0.682 AC: 30483 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 13334 AN: 25902

East Asian (EAS) AF: 0.839 AC: 33156 AN: 39516

South Asian (SAS) AF: 0.719 AC: 61425 AN: 85418

European-Finnish (FIN) AF: 0.657 AC: 35062 AN: 53372

Middle Eastern (MID) AF: 0.591 AC: 3373 AN: 5708

European-Non Finnish (NFE) AF: 0.625 AC: 671271 AN: 1074428

Other (OTH) AF: 0.648 AC: 38222 AN: 59010

GnomAD4 genome AF: 0.708 AC: 107670 AN: 152068 Hom.: 39187 Cov.: 32 AF XY: 0.709 AC XY: 52710 AN XY: 74306

African (AFR) AF: 0.877 AC: 36431 AN: 41538

American (AMR) AF: 0.662 AC: 10129 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1771 AN: 3466

East Asian (EAS) AF: 0.814 AC: 4194 AN: 5154

South Asian (SAS) AF: 0.725 AC: 3492 AN: 4814

European-Finnish (FIN) AF: 0.652 AC: 6872 AN: 10540

Middle Eastern (MID) AF: 0.582 AC: 170 AN: 292

European-Non Finnish (NFE) AF: 0.625 AC: 42484 AN: 67952

Other (OTH) AF: 0.665 AC: 1403 AN: 2110

Alfa AF: 0.633 Hom.: 46088

Bravo AF: 0.717

Asia WGS AF: 0.766 AC: 2662 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 09, 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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Methylcobalamin deficiency type cblG Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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	-0.90
CADD	Benign	0.28
DANN	Benign	0.38
PhyloP100		-0.20
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: rs3820571; hg19: chr1-237060433; COSMIC: COSV107465564;