rs1050993

chr1-236899005-A-Gchr1-236899005-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000254.3(MTR):c.*1361A>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 0.72 in 152,132 control chromosomes in the GnomAD database, including 40,669 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.72 (40667 hom., cov: 32)
  • Exomes 𝑓: 0.50 (2 hom.)
• Consequence: MTR NM_000254.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.452

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 1-236899005-A-G is Benign according to our data. Variant chr1-236899005-A-G is described in ClinVar as [Benign]. Clinvar id is 296611.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.903 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTR	NM_000254.3	c.*1361A>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.*1361A>G		3_prime_UTR_variant	33/33	1	NM_000254.3	P1

Frequencies

GnomAD3 genomes AF: 0.719 AC: 109337 AN: 151998 Hom.: 40616 Cov.: 32

Gnomad AFR AF: 0.911

Gnomad AMI AF: 0.800

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.813

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.651

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.627

Gnomad OTH AF: 0.676

GnomAD4 exome AF: 0.500 AC: 8 AN: 16 Hom.: 2 Cov.: 0 AF XY: 0.400 AC XY: 4 AN XY: 10

Gnomad4 FIN exome AF: 0.500

Gnomad4 OTH exome AF: 0.667

GnomAD4 genome AF: 0.720 AC: 109452 AN: 152116 Hom.: 40667 Cov.: 32 AF XY: 0.720 AC XY: 53555 AN XY: 74338

Gnomad4 AFR AF: 0.911

Gnomad4 AMR AF: 0.670

Gnomad4 ASJ AF: 0.534

Gnomad4 EAS AF: 0.813

Gnomad4 SAS AF: 0.727

Gnomad4 FIN AF: 0.651

Gnomad4 NFE AF: 0.627

Gnomad4 OTH AF: 0.679

Alfa AF: 0.632 Hom.: 29503

Bravo AF: 0.730

Asia WGS AF: 0.770 AC: 2677 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.71
Dann	Benign	0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1050993; hg19: chr1-237062305;