rs11799670

Variant names:

• chr1-236897797-A-G
• rs11799670
• NM_000254.3:c.*153A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000254.3(MTR):​c.*153A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 702,588 control chromosomes in the GnomAD database, including 1,960 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 0.076 (951 hom., cov: 31)
  • Exomes 𝑓: 0.037 (1009 hom.)
• Consequence: MTR NM_000254.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.590
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.*153A>G		3_prime_UTR_variant	Exon 33 of 33	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.*153A>G		3_prime_UTR_variant	Exon 33 of 33	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.*153A>G		3_prime_UTR_variant	Exon 20 of 20	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.0760 AC: 11557 AN: 152022 Hom.: 946 Cov.: 31

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0639

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.0405

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0594

GnomAD4 exome AF: 0.0372 AC: 20452 AN: 550444 Hom.: 1009 Cov.: 6 AF XY: 0.0401 AC XY: 11877 AN XY: 296240

African (AFR) AF: 0.203 AC: 2889 AN: 14200

American (AMR) AF: 0.0583 AC: 1436 AN: 24622

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 199 AN: 17180

East Asian (EAS) AF: 0.0645 AC: 2061 AN: 31968

South Asian (SAS) AF: 0.115 AC: 6216 AN: 54198

European-Finnish (FIN) AF: 0.0209 AC: 694 AN: 33156

Middle Eastern (MID) AF: 0.0526 AC: 119 AN: 2262

European-Non Finnish (NFE) AF: 0.0160 AC: 5504 AN: 343050

Other (OTH) AF: 0.0448 AC: 1334 AN: 29808

GnomAD4 genome AF: 0.0762 AC: 11592 AN: 152144 Hom.: 951 Cov.: 31 AF XY: 0.0772 AC XY: 5742 AN XY: 74398

African (AFR) AF: 0.199 AC: 8253 AN: 41450

American (AMR) AF: 0.0643 AC: 984 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3472

East Asian (EAS) AF: 0.0400 AC: 207 AN: 5172

South Asian (SAS) AF: 0.127 AC: 609 AN: 4812

European-Finnish (FIN) AF: 0.0232 AC: 246 AN: 10602

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0160 AC: 1087 AN: 68012

Other (OTH) AF: 0.0634 AC: 134 AN: 2112

Alfa AF: 0.0361 Hom.: 585

Bravo AF: 0.0833

Asia WGS AF: 0.0920 AC: 320 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 05, 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	-0.87
CADD	Benign	0.34
DANN	Benign	0.39
PhyloP100		-0.59
Mutation Taster		=100/0	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: rs11799670; hg19: chr1-237061097;