1-236795637-C-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.-67C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,608,430 control chromosomes in the GnomAD database, including 789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (89 hom., cov: 33)
  • Exomes 𝑓: 0.022 (700 hom.)
• Consequence: MTR NM_000254.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.740

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=-0.6).
• BP6: Variant 1-236795637-C-T is Benign according to our data. Variant chr1-236795637-C-T is described in ClinVar as [Benign]. Clinvar id is 296545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTR	NM_000254.3	c.-67C>T		5_prime_UTR_variant	1/33	ENST00000366577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTR	ENST00000366577.10	c.-67C>T		5_prime_UTR_variant	1/33	1	NM_000254.3	P1

Frequencies

GnomAD3 genomes AF: 0.0299 AC: 4555 AN: 152226 Hom.: 89 Cov.: 33

Gnomad AFR AF: 0.0432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0312

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.0655

Gnomad SAS AF: 0.0881

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0315 AC: 7617 AN: 241504 Hom.: 190 AF XY: 0.0329 AC XY: 4338 AN XY: 131980

Gnomad AFR exome AF: 0.0452

Gnomad AMR exome AF: 0.0275

Gnomad ASJ exome AF: 0.00950

Gnomad EAS exome AF: 0.0658

Gnomad SAS exome AF: 0.0757

Gnomad FIN exome AF: 0.0169

Gnomad NFE exome AF: 0.0176

Gnomad OTH exome AF: 0.0297

GnomAD4 exome AF: 0.0224 AC: 32577 AN: 1456086 Hom.: 700 Cov.: 31 AF XY: 0.0241 AC XY: 17443 AN XY: 724450

Gnomad4 AFR exome AF: 0.0466

Gnomad4 AMR exome AF: 0.0281

Gnomad4 ASJ exome AF: 0.0107

Gnomad4 EAS exome AF: 0.0711

Gnomad4 SAS exome AF: 0.0767

Gnomad4 FIN exome AF: 0.0164

Gnomad4 NFE exome AF: 0.0158

Gnomad4 OTH exome AF: 0.0245

GnomAD4 genome AF: 0.0299 AC: 4556 AN: 152344 Hom.: 89 Cov.: 33 AF XY: 0.0310 AC XY: 2308 AN XY: 74486

Gnomad4 AFR AF: 0.0432

Gnomad4 AMR AF: 0.0310

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.0657

Gnomad4 SAS AF: 0.0877

Gnomad4 FIN AF: 0.0162

Gnomad4 NFE AF: 0.0182

Gnomad4 OTH AF: 0.0345

Alfa AF: 0.0200 Hom.: 23

Bravo AF: 0.0309

Asia WGS AF: 0.0770 AC: 267 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Disorders of Intracellular Cobalamin Metabolism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

clinical testing

GeneDx

Nov 03, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	16
Dann	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs3738547; hg19: chr1-236958937; COSMIC: COSV63969145;