rs146019467

chr1-236824212-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000254.3(MTR):c.858C>T(p.Pro286=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00568 in 1,612,330 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0057 (56 hom.)
• Consequence: MTR NM_000254.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0530

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 1-236824212-C-T is Benign according to our data. Variant chr1-236824212-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 199000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236824212-C-T is described in Lovd as [Benign]. Variant chr1-236824212-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.053 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00541 (823/152112) while in subpopulation NFE AF= 0.00693 (471/67988). AF 95% confidence interval is 0.00641. There are 5 homozygotes in gnomad4. There are 456 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTR	NM_000254.3	c.858C>T	p.Pro286=	synonymous_variant	9/33	ENST00000366577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTR	ENST00000366577.10	c.858C>T	p.Pro286=	synonymous_variant	9/33	1	NM_000254.3	P1

Frequencies

GnomAD3 genomes AF: 0.00541 AC: 823 AN: 151994 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00693

Gnomad OTH AF: 0.00576

GnomAD3 exomes AF: 0.00596 AC: 1499 AN: 251448 Hom.: 14 AF XY: 0.00584 AC XY: 794 AN XY: 135910

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.0260

Gnomad NFE exome AF: 0.00659

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00571 AC: 8336 AN: 1460218 Hom.: 56 Cov.: 30 AF XY: 0.00570 AC XY: 4145 AN XY: 726566

Gnomad4 AFR exome AF: 0.000837

Gnomad4 AMR exome AF: 0.00268

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00128

Gnomad4 FIN exome AF: 0.0245

Gnomad4 NFE exome AF: 0.00583

Gnomad4 OTH exome AF: 0.00451

GnomAD4 genome AF: 0.00541 AC: 823 AN: 152112 Hom.: 5 Cov.: 31 AF XY: 0.00613 AC XY: 456 AN XY: 74352

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0252

Gnomad4 NFE AF: 0.00693

Gnomad4 OTH AF: 0.00570

Alfa AF: 0.00578 Hom.: 0

Bravo AF: 0.00323

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00567

EpiControl AF: 0.00545

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2016	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	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MTR: BP4, BP7, BS2 -

Methylcobalamin deficiency type cblG Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	7.7
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs146019467; hg19: chr1-236987512; COSMIC: COSV63968254; COSMIC: COSV63968254;