1-236901326-T-G

Position:

• chr1-236901326-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000366577.10(MTR):​c.*3682T>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 0.563 in 151,946 control chromosomes in the GnomAD database, including 24,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24402 hom., cov: 31)
  • Exomes 𝑓: 0.58 (49 hom.)
• Consequence: MTR ENST00000366577.10 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.52

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 1-236901326-T-G is Benign according to our data. Variant chr1-236901326-T-G is described in ClinVar as [Benign]. Clinvar id is 296655.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	Protein	UniProt
MTR	NM_000254.3	c.*3682T>G		3_prime_UTR_variant	33/33	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.*3682T>G		3_prime_UTR_variant	33/33	1	NM_000254.3	ENSP00000355536	P1

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85288 AN: 151540 Hom.: 24374 Cov.: 31

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.766

Gnomad AMR AF: 0.585

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.610

Gnomad FIN AF: 0.635

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.530

GnomAD4 exome AF: 0.583 AC: 168 AN: 288 Hom.: 49 Cov.: 0 AF XY: 0.549 AC XY: 100 AN XY: 182

Gnomad4 AMR exome AF: 1.00

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.623

Gnomad4 NFE exome AF: 0.519

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.563 AC: 85356 AN: 151658 Hom.: 24402 Cov.: 31 AF XY: 0.566 AC XY: 41962 AN XY: 74136

Gnomad4 AFR AF: 0.468

Gnomad4 AMR AF: 0.586

Gnomad4 ASJ AF: 0.500

Gnomad4 EAS AF: 0.556

Gnomad4 SAS AF: 0.610

Gnomad4 FIN AF: 0.635

Gnomad4 NFE AF: 0.602

Gnomad4 OTH AF: 0.534

Alfa AF: 0.475 Hom.: 1558

Bravo AF: 0.552

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 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.8
DANN	Benign	0.52

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: rs6676866; hg19: chr1-237064626;