rs2853522

Positions:

• chr1-236897756-A-C
• chr1-236897756-A-G
• chr1-236897756-A-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.*112A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 898,370 control chromosomes in the GnomAD database, including 159,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24373 hom., cov: 30)
  • Exomes 𝑓: 0.60 (134675 hom.)
• Consequence: MTR NM_000254.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.15

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=-0.95).
• BP6: Variant 1-236897756-A-C is Benign according to our data. Variant chr1-236897756-A-C is described in ClinVar as [Benign]. Clinvar id is 296587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTR	NM_000254.3	c.*112A>C		3_prime_UTR_variant	33/33	ENST00000366577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTR	ENST00000366577.10	c.*112A>C		3_prime_UTR_variant	33/33	1	NM_000254.3	P1

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85176 AN: 151578 Hom.: 24345 Cov.: 30

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.766

Gnomad AMR AF: 0.585

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.615

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.532

GnomAD4 exome AF: 0.597 AC: 445603 AN: 746674 Hom.: 134675 Cov.: 10 AF XY: 0.598 AC XY: 236736 AN XY: 395782

Gnomad4 AFR exome AF: 0.462

Gnomad4 AMR exome AF: 0.630

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.619

Gnomad4 SAS exome AF: 0.628

Gnomad4 FIN exome AF: 0.639

Gnomad4 NFE exome AF: 0.596

Gnomad4 OTH exome AF: 0.575

GnomAD4 genome AF: 0.562 AC: 85245 AN: 151696 Hom.: 24373 Cov.: 30 AF XY: 0.565 AC XY: 41910 AN XY: 74126

Gnomad4 AFR AF: 0.464

Gnomad4 AMR AF: 0.586

Gnomad4 ASJ AF: 0.500

Gnomad4 EAS AF: 0.558

Gnomad4 SAS AF: 0.615

Gnomad4 FIN AF: 0.637

Gnomad4 NFE AF: 0.603

Gnomad4 OTH AF: 0.536

Alfa AF: 0.580 Hom.: 41465

Bravo AF: 0.552

Asia WGS AF: 0.579 AC: 2012 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -

Disorders of Intracellular Cobalamin Metabolism Benign:1

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 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	-0.95
CADD	Benign	2.9
DANN	Benign	0.56

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: rs2853522; hg19: chr1-237061056;