rs1770449

Positions:

• chr1-236874861-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000254.3(MTR):​c.2594+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 1,611,418 control chromosomes in the GnomAD database, including 99,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7105 hom., cov: 32)
  • Exomes 𝑓: 0.35 (92293 hom.)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.157

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-236874861-T-C is Benign according to our data. Variant chr1-236874861-T-C is described in ClinVar as [Benign]. Clinvar id is 138288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236874861-T-C is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
MTR	NM_000254.3	c.2594+15T>C		intron_variant		ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.2594+15T>C		intron_variant		1	NM_000254.3	ENSP00000355536	P1

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41912 AN: 152062 Hom.: 7111 Cov.: 32

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.314

GnomAD3 exomes AF: 0.322 AC: 80647 AN: 250476 Hom.: 14004 AF XY: 0.328 AC XY: 44469 AN XY: 135398

Gnomad AFR exome AF: 0.0701

Gnomad AMR exome AF: 0.313

Gnomad ASJ exome AF: 0.463

Gnomad EAS exome AF: 0.192

Gnomad SAS exome AF: 0.279

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.375

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.349 AC: 509353 AN: 1459238 Hom.: 92293 Cov.: 34 AF XY: 0.348 AC XY: 252911 AN XY: 725980

Gnomad4 AFR exome AF: 0.0649

Gnomad4 AMR exome AF: 0.311

Gnomad4 ASJ exome AF: 0.460

Gnomad4 EAS exome AF: 0.161

Gnomad4 SAS exome AF: 0.280

Gnomad4 FIN exome AF: 0.343

Gnomad4 NFE exome AF: 0.369

Gnomad4 OTH exome AF: 0.341

GnomAD4 genome AF: 0.275 AC: 41900 AN: 152180 Hom.: 7105 Cov.: 32 AF XY: 0.274 AC XY: 20417 AN XY: 74396

Gnomad4 AFR AF: 0.0815

Gnomad4 AMR AF: 0.323

Gnomad4 ASJ AF: 0.466

Gnomad4 EAS AF: 0.187

Gnomad4 SAS AF: 0.273

Gnomad4 FIN AF: 0.348

Gnomad4 NFE AF: 0.369

Gnomad4 OTH AF: 0.311

Alfa AF: 0.346 Hom.: 3297

Bravo AF: 0.264

Asia WGS AF: 0.228 AC: 795 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Methylcobalamin deficiency type cblG Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Disorders of Intracellular Cobalamin Metabolism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.9
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1770449; hg19: chr1-237038161; COSMIC: COSV63964725;