rs1050993

Variant names:

• chr1-236899005-A-G
• rs1050993
• NM_000254.3:c.*1361A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-236899005-A-G
• chr1-236899005-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.452
• Publications: 24 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 -20 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 VariationId is 296611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.903 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.*1361A>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.*1361A>G		3_prime_UTR_variant	Exon 33 of 33	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.*1361A>G		3_prime_UTR_variant	Exon 20 of 20	1		ENSP00000355535.3

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 4 AN: 8

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.667 AC: 4 AN: 6

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

African (AFR) AF: 0.911 AC: 37839 AN: 41542

American (AMR) AF: 0.670 AC: 10233 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1854 AN: 3470

East Asian (EAS) AF: 0.813 AC: 4208 AN: 5174

South Asian (SAS) AF: 0.727 AC: 3511 AN: 4830

European-Finnish (FIN) AF: 0.651 AC: 6861 AN: 10536

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.627 AC: 42596 AN: 67966

Other (OTH) AF: 0.679 AC: 1434 AN: 2112

Alfa AF: 0.644 Hom.: 40613

Bravo AF: 0.730

Asia WGS AF: 0.770 AC: 2677 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

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.71
DANN	Benign	0.32
PhyloP100		-0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1050993; hg19: chr1-237062305;