rs3738547

Variant names:

• chr1-236795637-C-T
• rs3738547
• NM_000254.3:c.-67C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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:3
• Conservation: PhyloP100: 0.740
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• methylcobalamin deficiency type cblG

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.02).
• 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 rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.-67C>T		5_prime_UTR_variant	Exon 1 of 33	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.-67C>T		5_prime_UTR_variant	Exon 1 of 33	1	NM_000254.3	ENSP00000355536.5

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

GnomAD2 exomes AF: 0.0315 AC: 7617 AN: 241504 AF XY: 0.0329

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 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

African (AFR) AF: 0.0466 AC: 1557 AN: 33420

American (AMR) AF: 0.0281 AC: 1251 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 280 AN: 26070

East Asian (EAS) AF: 0.0711 AC: 2810 AN: 39512

South Asian (SAS) AF: 0.0767 AC: 6599 AN: 86042

European-Finnish (FIN) AF: 0.0164 AC: 808 AN: 49408

Middle Eastern (MID) AF: 0.0421 AC: 241 AN: 5728

European-Non Finnish (NFE) AF: 0.0158 AC: 17557 AN: 1111202

Other (OTH) AF: 0.0245 AC: 1474 AN: 60214

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

African (AFR) AF: 0.0432 AC: 1796 AN: 41590

American (AMR) AF: 0.0310 AC: 475 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3470

East Asian (EAS) AF: 0.0657 AC: 339 AN: 5162

South Asian (SAS) AF: 0.0877 AC: 424 AN: 4832

European-Finnish (FIN) AF: 0.0162 AC: 172 AN: 10630

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0182 AC: 1237 AN: 68032

Other (OTH) AF: 0.0345 AC: 73 AN: 2114

Alfa AF: 0.0217 Hom.: 99

Bravo AF: 0.0309

Asia WGS AF: 0.0770 AC: 267 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 03, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Disorders of Intracellular Cobalamin Metabolism Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.96
PhyloP100		0.74
PromoterAI		0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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