rs2853522

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.15

Publications

17 publications found

Variant links:

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

MTR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000254.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MTR	NM_000254.3	MANE Select	c.*112A>C	3_prime_UTR	Exon 33 of 33	NP_000245.2
MTR	NM_001291939.1		c.*112A>C	3_prime_UTR	Exon 32 of 32	NP_001278868.1
MTR	NM_001410942.1		c.*112A>C	3_prime_UTR	Exon 31 of 31	NP_001397871.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MTR	ENST00000366577.10	TSL:1 MANE Select	c.*112A>C	3_prime_UTR	Exon 33 of 33	ENSP00000355536.5
MTR	ENST00000535889.6	TSL:1	c.*112A>C	3_prime_UTR	Exon 32 of 32	ENSP00000441845.1
MTR	ENST00000366576.3	TSL:1	c.*112A>C	3_prime_UTR	Exon 20 of 20	ENSP00000355535.3

Frequencies

GnomAD3 genomes

AF:

0.562

AC:

85176

AN:

151578

Hom.:

24345

Cov.:

show subpopulations

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.:

AF XY:

0.598

AC XY:

236736

AN XY:

395782

show subpopulations

African (AFR)

AF:

0.462

AC:

8661

AN:

18742

American (AMR)

AF:

0.630

AC:

22405

AN:

35576

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

10363

AN:

20728

East Asian (EAS)

AF:

0.619

AC:

21926

AN:

35446

South Asian (SAS)

AF:

0.628

AC:

41571

AN:

66212

European-Finnish (FIN)

AF:

0.639

AC:

26038

AN:

40762

Middle Eastern (MID)

AF:

0.527

AC:

1666

AN:

3160

European-Non Finnish (NFE)

AF:

0.596

AC:

291916

AN:

489430

Other (OTH)

AF:

0.575

AC:

21057

AN:

36618

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

8971

17942

26913

35884

44855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4460

8920

13380

17840

22300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.562

AC:

85245

AN:

151696

Hom.:

24373

Cov.:

AF XY:

0.565

AC XY:

41910

AN XY:

74126

show subpopulations

African (AFR)

AF:

0.464

AC:

19156

AN:

41302

American (AMR)

AF:

0.586

AC:

8935

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

1735

AN:

3470

East Asian (EAS)

AF:

0.558

AC:

2868

AN:

5138

South Asian (SAS)

AF:

0.615

AC:

2947

AN:

4790

European-Finnish (FIN)

AF:

0.637

AC:

6687

AN:

10494

Middle Eastern (MID)

AF:

0.500

AC:

147

AN:

294

European-Non Finnish (NFE)

AF:

0.603

AC:

40947

AN:

67938

Other (OTH)

AF:

0.536

AC:

1126

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1849

3698

5548

7397

9246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

748

1496

2244

2992

3740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.578

Hom.:

69331

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jun 29, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Disorders of Intracellular Cobalamin Metabolism

Benign:1

Jan 13, 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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

2.9

(source)

DANN

Benign

0.56

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over