1-236808698-C-T

Position:

chr1-236808698-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000366577.10(MTR):c.340-6C>T variant causes a splice region, splice polypyrimidine tract, 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
ENST00000366577.10 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00002343

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.58

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 138287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236808698-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
MTR	NM_000254.3 linkuse as main transcript	c.340-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10 linkuse as main transcript	c.340-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000254.3	ENSP00000355536	P1	Q99707-1

Frequencies

GnomAD3 genomes

AF:

0.0549

AC:

8357

AN:

152160

Hom.:

383

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0378

AC:

9494

AN:

251404

Hom.:

328

AF XY:

0.0377

AC XY:

5119

AN XY:

135870

show subpopulations

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 SAS exome

AF:

0.0761

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.:

AF XY:

0.0279

AC XY:

20257

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.132

Gnomad4 AMR exome

AF:

0.0330

Gnomad4 ASJ exome

AF:

0.0101

Gnomad4 EAS exome

AF:

0.0632

Gnomad4 SAS exome

AF:

0.0770

Gnomad4 FIN exome

AF:

0.0168

Gnomad4 NFE exome

AF:

0.0182

Gnomad4 OTH exome

AF:

0.0320

GnomAD4 genome

AF:

0.0550

AC:

8376

AN:

152278

Hom.:

385

Cov.:

AF XY:

0.0553

AC XY:

4121

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.127

Gnomad4 AMR

AF:

0.0402

Gnomad4 ASJ

AF:

0.00864

Gnomad4 EAS

AF:

0.0540

Gnomad4 SAS

AF:

0.0896

Gnomad4 FIN

AF:

0.0165

Gnomad4 NFE

AF:

0.0211

Gnomad4 OTH

AF:

0.0506

Alfa

AF:

0.0294

Hom.:

196

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

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 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. -

Methylcobalamin deficiency type cblG

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

-0.82

CADD

Benign

6.1

DANN

Benign

0.54

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over