1-236795503-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000254.3(MTR):c.-201C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,521,628 control chromosomes in the GnomAD database, including 301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 35 hom., cov: 33)

Exomes 𝑓: 0.018 ( 266 hom. )

Consequence

MTR
NM_000254.3 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.48

Publications

2 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 (REVEL=0.005).

BP6

Variant 1-236795503-C-G is Benign according to our data. Variant chr1-236795503-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 296538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0147 (2242/152338) while in subpopulation NFE AF = 0.0232 (1579/68020). AF 95% confidence interval is 0.0223. There are 35 homozygotes in GnomAd4. There are 1056 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3 link	c.-201C>G		5_prime_UTR_variant	Exon 1 of 33	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.-201C>G		5_prime_UTR_variant	Exon 1 of 33	1	NM_000254.3	ENSP00000355536.5		Q99707-1

Frequencies

GnomAD3 genomes

AF:

0.0147

AC:

2241

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00306

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0190

Gnomad ASJ

AF:

0.0259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00885

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0232

Gnomad OTH

AF:

0.0191

GnomAD2 exomes

AF:

0.0142

AC:

1926

AN:

135266

AF XY:

0.0139

show subpopulations

Gnomad AFR exome

AF:

0.00259

Gnomad AMR exome

AF:

0.0134

Gnomad ASJ exome

AF:

0.0223

Gnomad EAS exome

AF:

0.0000930

Gnomad FIN exome

AF:

0.00848

Gnomad NFE exome

AF:

0.0226

Gnomad OTH exome

AF:

0.0175

GnomAD4 exome

AF:

0.0180

AC:

24613

AN:

1369290

Hom.:

266

Cov.:

AF XY:

0.0176

AC XY:

11887

AN XY:

675526

show subpopulations

African (AFR)

AF:

0.00311

AC:

AN:

31214

American (AMR)

AF:

0.0136

AC:

480

AN:

35192

Ashkenazi Jewish (ASJ)

AF:

0.0224

AC:

553

AN:

24712

East Asian (EAS)

AF:

0.0000571

AC:

AN:

35014

South Asian (SAS)

AF:

0.00287

AC:

225

AN:

78378

European-Finnish (FIN)

AF:

0.0102

AC:

336

AN:

32784

Middle Eastern (MID)

AF:

0.0251

AC:

141

AN:

5614

European-Non Finnish (NFE)

AF:

0.0204

AC:

21804

AN:

1069414

Other (OTH)

AF:

0.0171

AC:

975

AN:

56968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

1495

2989

4484

5978

7473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0147

AC:

2242

AN:

152338

Hom.:

Cov.:

AF XY:

0.0142

AC XY:

1056

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00305

AC:

127

AN:

41592

American (AMR)

AF:

0.0190

AC:

291

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00186

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00885

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0232

AC:

1579

AN:

68020

Other (OTH)

AF:

0.0189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

120

240

359

479

599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0191

Hom.:

Bravo

AF:

0.0146

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 29, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.9

(source)

DANN

Benign

0.64

PhyloP100

-1.5

PromoterAI

0.14

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=297/3

polymorphism

(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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1-236795503-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over