Genetic Variant MTR:c.1516-271T>C (chr1-236850073-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000254.3(MTR):c.1516-271T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 152,006 control chromosomes in the GnomAD database, including 10,216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.35 ( 10216 hom., cov: 31)

Consequence

MTR
NM_000254.3 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.11

Publications

1 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 1-236850073-T-C is Benign according to our data. Variant chr1-236850073-T-C is described in ClinVar as Benign. ClinVar VariationId is 1280439.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3 link	c.1516-271T>C		intron_variant	Intron 15 of 32	ENST00000366577.10	NP_000245.2	Q99707-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10 link	c.1516-271T>C		intron_variant	Intron 15 of 32	1	NM_000254.3	ENSP00000355536.5		Q99707-1
MTR	ENST00000366576.3 link	c.178-271T>C		intron_variant	Intron 2 of 19	1		ENSP00000355535.3		B1ANE3

Frequencies

GnomAD3 genomes

AF:

0.352

AC:

53456

AN:

151888

Hom.:

10212

Cov.:

show subpopulations

Gnomad AFR

AF:

0.204

Gnomad AMI

AF:

0.573

Gnomad AMR

AF:

0.409

Gnomad ASJ

AF:

0.321

Gnomad EAS

AF:

0.432

Gnomad SAS

AF:

0.295

Gnomad FIN

AF:

0.446

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.411

Gnomad OTH

AF:

0.354

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.352

AC:

53486

AN:

152006

Hom.:

10216

Cov.:

AF XY:

0.353

AC XY:

26256

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.204

AC:

8446

AN:

41474

American (AMR)

AF:

0.410

AC:

6254

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.321

AC:

1113

AN:

3468

East Asian (EAS)

AF:

0.434

AC:

2237

AN:

5156

South Asian (SAS)

AF:

0.297

AC:

1429

AN:

4818

European-Finnish (FIN)

AF:

0.446

AC:

4705

AN:

10544

Middle Eastern (MID)

AF:

0.330

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.411

AC:

27942

AN:

67966

Other (OTH)

AF:

0.350

AC:

740

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1687

3374

5062

6749

8436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

540

1080

1620

2160

2700

<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:

0.382

Hom.:

1841

Bravo

AF:

0.347

Asia WGS

AF:

0.354

AC:

1228

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 07, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

9.6

(source)

DANN

Benign

0.68

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over