Genetic Variant MTR:c.1696-193C>T (chr1-236852328-C-T) – 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.1696-193C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 151,666 control chromosomes in the GnomAD database, including 13,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.43 ( 13924 hom., cov: 30)

Consequence

MTR
NM_000254.3 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0500

Publications

8 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=-0.95).

BP6

Variant 1-236852328-C-T is Benign according to our data. Variant chr1-236852328-C-T is described in ClinVar as [Benign]. Clinvar id is 1262193.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3 link	c.1696-193C>T		intron_variant	Intron 16 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.1696-193C>T		intron_variant	Intron 16 of 32	1	NM_000254.3	ENSP00000355536.5		Q99707-1
MTR	ENST00000366576.3 link	c.358-193C>T		intron_variant	Intron 3 of 19	1		ENSP00000355535.3		B1ANE3

Frequencies

GnomAD3 genomes

AF:

0.426

AC:

64501

AN:

151548

Hom.:

13917

Cov.:

show subpopulations

Gnomad AFR

AF:

0.405

Gnomad AMI

AF:

0.607

Gnomad AMR

AF:

0.456

Gnomad ASJ

AF:

0.310

Gnomad EAS

AF:

0.458

Gnomad SAS

AF:

0.383

Gnomad FIN

AF:

0.450

Gnomad MID

AF:

0.367

Gnomad NFE

AF:

0.432

Gnomad OTH

AF:

0.421

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

GnomAD4 genome

AF:

0.426

AC:

64548

AN:

151666

Hom.:

13924

Cov.:

AF XY:

0.426

AC XY:

31523

AN XY:

74084

show subpopulations

African (AFR)

AF:

0.405

AC:

16725

AN:

41312

American (AMR)

AF:

0.456

AC:

6938

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.310

AC:

1076

AN:

3466

East Asian (EAS)

AF:

0.460

AC:

2366

AN:

5148

South Asian (SAS)

AF:

0.384

AC:

1845

AN:

4800

European-Finnish (FIN)

AF:

0.450

AC:

4715

AN:

10482

Middle Eastern (MID)

AF:

0.374

AC:

110

AN:

294

European-Non Finnish (NFE)

AF:

0.432

AC:

29342

AN:

67930

Other (OTH)

AF:

0.417

AC:

877

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1885

3770

5655

7540

9425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

618

1236

1854

2472

3090

<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:

0.425

Hom.:

43048

Bravo

AF:

0.430

Asia WGS

AF:

0.426

AC:

1482

AN:

3478

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

-0.95

CADD

Benign

0.48

(source)

DANN

Benign

0.83

PhyloP100

0.050

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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