1-236897133-G-T

Position:

• chr1-236897133-G-T

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.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

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=-0.9).
• BP6: Variant 1-236897133-G-T is Benign according to our data. Variant chr1-236897133-G-T is described in ClinVar as [Benign]. Clinvar id is 138285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236897133-G-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
MTR	NM_000254.3	c.3711+15G>T		intron_variant		ENST00000366577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTR	ENST00000366577.10	c.3711+15G>T		intron_variant		1	NM_000254.3	P1

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

GnomAD3 exomes AF: 0.670 AC: 168298 AN: 251296 Hom.: 57358 AF XY: 0.664 AC XY: 90179 AN XY: 135828

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 SAS exome AF: 0.719

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

Gnomad4 AFR exome AF: 0.889

Gnomad4 AMR exome AF: 0.682

Gnomad4 ASJ exome AF: 0.515

Gnomad4 EAS exome AF: 0.839

Gnomad4 SAS exome AF: 0.719

Gnomad4 FIN exome AF: 0.657

Gnomad4 NFE exome AF: 0.625

Gnomad4 OTH exome AF: 0.648

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

Gnomad4 AFR AF: 0.877

Gnomad4 AMR AF: 0.662

Gnomad4 ASJ AF: 0.511

Gnomad4 EAS AF: 0.814

Gnomad4 SAS AF: 0.725

Gnomad4 FIN AF: 0.652

Gnomad4 NFE AF: 0.625

Gnomad4 OTH AF: 0.665

Alfa AF: 0.624 Hom.: 37014

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 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, 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	-	- -

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	-0.90
CADD	Benign	0.28
DANN	Benign	0.38

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: rs3820571; hg19: chr1-237060433;