rs1805087

Variant names:

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.2756A>G(p.Asp919Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,590,910 control chromosomes in the GnomAD database, including 34,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3656 hom., cov: 32)

Exomes 𝑓: 0.20 ( 30392 hom. )

Consequence

MTR
NM_000254.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:7O:1

Conservation

PhyloP100: 8.54

Publications

674 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 (MetaRNN=0.0016700923).

BP6

Variant 1-236885200-A-G is Benign according to our data. Variant chr1-236885200-A-G is described in ClinVar as Benign. ClinVar VariationId is 138289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.298 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	HGVSp	Effect	Exon Rank	Protein
MTR	NM_000254.3	MANE Select	c.2756A>G	p.Asp919Gly	missense	Exon 26 of 33	NP_000245.2
MTR	NM_001291939.1		c.2603A>G	p.Asp868Gly	missense	Exon 25 of 32	NP_001278868.1
MTR	NM_001410942.1		c.2567A>G	p.Asp856Gly	missense	Exon 24 of 31	NP_001397871.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTR	ENST00000366577.10	TSL:1 MANE Select	c.2756A>G	p.Asp919Gly	missense	Exon 26 of 33	ENSP00000355536.5
MTR	ENST00000535889.6	TSL:1	c.2603A>G	p.Asp868Gly	missense	Exon 25 of 32	ENSP00000441845.1
MTR	ENST00000366576.3	TSL:1	c.1418A>G	p.Asp473Gly	missense	Exon 13 of 20	ENSP00000355535.3

Frequencies

GnomAD3 genomes

AF:

0.213

AC:

32337

AN:

152018

Hom.:

3645

Cov.:

show subpopulations

Gnomad AFR

AF:

0.263

Gnomad AMI

AF:

0.190

Gnomad AMR

AF:

0.184

Gnomad ASJ

AF:

0.175

Gnomad EAS

AF:

0.122

Gnomad SAS

AF:

0.313

Gnomad FIN

AF:

0.189

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.196

Gnomad OTH

AF:

0.188

GnomAD2 exomes

AF:

0.203

AC:

50989

AN:

251124

AF XY:

0.208

show subpopulations

Gnomad AFR exome

AF:

0.266

Gnomad AMR exome

AF:

0.184

Gnomad ASJ exome

AF:

0.168

Gnomad EAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.192

Gnomad NFE exome

AF:

0.191

Gnomad OTH exome

AF:

0.197

GnomAD4 exome

AF:

0.200

AC:

287192

AN:

1438774

Hom.:

30392

Cov.:

AF XY:

0.203

AC XY:

145505

AN XY:

717146

show subpopulations

African (AFR)

AF:

0.268

AC:

8836

AN:

32964

American (AMR)

AF:

0.182

AC:

8118

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

4490

AN:

26030

East Asian (EAS)

AF:

0.151

AC:

5963

AN:

39616

South Asian (SAS)

AF:

0.307

AC:

26311

AN:

85704

European-Finnish (FIN)

AF:

0.197

AC:

10471

AN:

53230

Middle Eastern (MID)

AF:

0.210

AC:

1203

AN:

5722

European-Non Finnish (NFE)

AF:

0.192

AC:

209736

AN:

1091302

Other (OTH)

AF:

0.203

AC:

12064

AN:

59506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

10623

21245

31868

42490

53113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7288

14576

21864

29152

36440

<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:

0.213

AC:

32375

AN:

152136

Hom.:

3656

Cov.:

AF XY:

0.214

AC XY:

15932

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.263

AC:

10896

AN:

41484

American (AMR)

AF:

0.184

AC:

2810

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.175

AC:

608

AN:

3470

East Asian (EAS)

AF:

0.121

AC:

627

AN:

5174

South Asian (SAS)

AF:

0.311

AC:

1500

AN:

4820

European-Finnish (FIN)

AF:

0.189

AC:

2001

AN:

10592

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.196

AC:

13298

AN:

67986

Other (OTH)

AF:

0.196

AC:

414

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1315

2629

3944

5258

6573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

348

696

1044

1392

1740

<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:

0.196

Hom.:

15608

Bravo

AF:

0.209

TwinsUK

AF:

0.203

AC:

752

ALSPAC

AF:

0.199

AC:

768

ESP6500AA

AF:

0.264

AC:

1164

ESP6500EA

AF:

0.198

AC:

1702

ExAC

AF:

0.209

AC:

25325

Asia WGS

AF:

0.218

AC:

758

AN:

3478

EpiCase

AF:

0.182

EpiControl

AF:

0.182

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Methylcobalamin deficiency type cblG (2)

not provided (2)

Disorders of Intracellular Cobalamin Metabolism (1)

Gastrointestinal stromal tumor (1)

MTR-related disorder (1)

not specified (1)

Neural tube defects, folate-sensitive, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

8.5

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-4.0

REVEL

Uncertain

0.34

Sift

Benign

0.19

Sift4G

Benign

0.24

Polyphen

0.16

Vest4

0.22

MPC

0.70

ClinPred

0.040

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.58

Mutation Taster

=73/27

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

Computational scores

Splicing

Publications

Other links and lift over