rs115186224

chr1-236831958-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000254.3(MTR):c.1076-8C>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 0.00378 in 1,611,136 control chromosomes in the GnomAD database, including 26 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (24 hom.)
• Consequence: MTR NM_000254.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001340
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.610

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 1-236831958-C-T is Benign according to our data. Variant chr1-236831958-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 296558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236831958-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00311 (474/152302) while in subpopulation NFE AF= 0.00548 (373/68030). AF 95% confidence interval is 0.00502. There are 2 homozygotes in gnomad4. There are 199 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTR	NM_000254.3	c.1076-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000366577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTR	ENST00000366577.10	c.1076-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000254.3	P1

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 475 AN: 152184 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00548

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00259 AC: 651 AN: 251180 Hom.: 3 AF XY: 0.00243 AC XY: 330 AN XY: 135754

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.00480

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00385 AC: 5619 AN: 1458834 Hom.: 24 Cov.: 30 AF XY: 0.00377 AC XY: 2733 AN XY: 725896

Gnomad4 AFR exome AF: 0.000629

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00211

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.00105

Gnomad4 NFE exome AF: 0.00471

Gnomad4 OTH exome AF: 0.00272

GnomAD4 genome AF: 0.00311 AC: 474 AN: 152302 Hom.: 2 Cov.: 33 AF XY: 0.00267 AC XY: 199 AN XY: 74482

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00548

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00404 Hom.: 2

Bravo AF: 0.00280

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00545

EpiControl AF: 0.00379

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	MTR: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2018

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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Methylcobalamin deficiency type cblG Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
Cadd	Benign	14
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0013
dbscSNV1_RF	Benign	0.064
SpliceAI score (max)		0.15		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: rs115186224; hg19: chr1-236995258;