rs11799670

chr1-236897797-A-G

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.*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. Variant has been reported in ClinVar as Benign (★★).

• 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:2
• Conservation: PhyloP100: -0.590

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=-0.87).
• BP6: Variant 1-236897797-A-G is Benign according to our data. Variant chr1-236897797-A-G is described in ClinVar as [Benign]. Clinvar id is 296588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	UniProt
MTR	NM_000254.3	c.*153A>G		3_prime_UTR_variant	33/33	ENST00000366577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTR	ENST00000366577.10	c.*153A>G		3_prime_UTR_variant	33/33	1	NM_000254.3	P1

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

Gnomad4 AFR exome AF: 0.203

Gnomad4 AMR exome AF: 0.0583

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.0645

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.0209

Gnomad4 NFE exome AF: 0.0160

Gnomad4 OTH exome AF: 0.0448

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

Gnomad4 AFR AF: 0.199

Gnomad4 AMR AF: 0.0643

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.0400

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.0232

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.0634

Alfa AF: 0.0309 Hom.: 281

Bravo AF: 0.0833

Asia WGS AF: 0.0920 AC: 320 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

Jul 05, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.34
Dann	Benign	0.39

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: rs11799670; hg19: chr1-237061097;