rs16879334

Variant names:

Variant summary

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

The NM_002454.3(MTRR):c.1349C>G(p.Pro450Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0376 in 1,605,388 control chromosomes in the GnomAD database, including 2,101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P450S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.041 ( 251 hom., cov: 30)

Exomes 𝑓: 0.037 ( 1850 hom. )

Consequence

MTRR
NM_002454.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.38

Publications

35 publications found

Variant links:

Genes affected

MTRR (HGNC:7473): (5-methyltetrahydrofolate-homocysteine methyltransferase reductase) This gene encodes a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases. This protein functions in the synthesis of methionine by regenerating methionine synthase to a functional state. Because methionine synthesis requires methyl-group transfer by a folate donor, activity of the encoded enzyme is important for folate metabolism and cellular methylation. Mutations in this gene can cause homocystinuria-megaloblastic anemia, cbl E type. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2015]

MTRR Gene-Disease associations (from GenCC):

methylcobalamin deficiency type cblE
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet

MTRR 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=0.0036573112).

BP6

Variant 5-7891393-C-G is Benign according to our data. Variant chr5-7891393-C-G is described in ClinVar as Benign. ClinVar VariationId is 138294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002454.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTRR	NM_002454.3	MANE Select	c.1349C>G	p.Pro450Arg	missense	Exon 10 of 15	NP_002445.2
MTRR	NM_001364440.2		c.1349C>G	p.Pro450Arg	missense	Exon 10 of 15	NP_001351369.1
MTRR	NM_001364441.2		c.1349C>G	p.Pro450Arg	missense	Exon 10 of 15	NP_001351370.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTRR	ENST00000440940.7	TSL:1 MANE Select	c.1349C>G	p.Pro450Arg	missense	Exon 10 of 15	ENSP00000402510.2
MTRR	ENST00000264668.6	TSL:1	c.1430C>G	p.Pro477Arg	missense	Exon 10 of 15	ENSP00000264668.2
MTRR	ENST00000513439.5	TSL:1	n.*1056C>G		non_coding_transcript_exon	Exon 10 of 15	ENSP00000426710.1

Frequencies

GnomAD3 genomes

AF:

0.0407

AC:

6126

AN:

150694

Hom.:

250

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0133

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0862

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.184

Gnomad SAS

AF:

0.0379

Gnomad FIN

AF:

0.0704

Gnomad MID

AF:

0.00962

Gnomad NFE

AF:

0.0333

Gnomad OTH

AF:

0.0394

GnomAD2 exomes

AF:

0.0587

AC:

14689

AN:

250328

AF XY:

0.0535

show subpopulations

Gnomad AFR exome

AF:

0.0131

Gnomad AMR exome

AF:

0.135

Gnomad ASJ exome

AF:

0.0130

Gnomad EAS exome

AF:

0.180

Gnomad FIN exome

AF:

0.0691

Gnomad NFE exome

AF:

0.0322

Gnomad OTH exome

AF:

0.0451

GnomAD4 exome

AF:

0.0372

AC:

54171

AN:

1454594

Hom.:

1850

Cov.:

AF XY:

0.0368

AC XY:

26646

AN XY:

724012

show subpopulations

African (AFR)

AF:

0.0103

AC:

344

AN:

33380

American (AMR)

AF:

0.132

AC:

5861

AN:

44432

Ashkenazi Jewish (ASJ)

AF:

0.0131

AC:

343

AN:

26088

East Asian (EAS)

AF:

0.172

AC:

6769

AN:

39410

South Asian (SAS)

AF:

0.0334

AC:

2869

AN:

85974

European-Finnish (FIN)

AF:

0.0671

AC:

3570

AN:

53210

Middle Eastern (MID)

AF:

0.00660

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0290

AC:

32094

AN:

1106248

Other (OTH)

AF:

0.0380

AC:

2283

AN:

60094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.403

Heterozygous variant carriers

2192

4385

6577

8770

10962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1286

2572

3858

5144

6430

<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:

0.0406

AC:

6128

AN:

150794

Hom.:

251

Cov.:

AF XY:

0.0439

AC XY:

3229

AN XY:

73578

show subpopulations

African (AFR)

AF:

0.0135

AC:

552

AN:

41002

American (AMR)

AF:

0.0861

AC:

1301

AN:

15112

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3470

East Asian (EAS)

AF:

0.184

AC:

939

AN:

5100

South Asian (SAS)

AF:

0.0378

AC:

180

AN:

4758

European-Finnish (FIN)

AF:

0.0704

AC:

719

AN:

10216

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0333

AC:

2260

AN:

67834

Other (OTH)

AF:

0.0381

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

270

540

809

1079

1349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<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:

0.0344

Hom.:

Bravo

AF:

0.0412

TwinsUK

AF:

0.0286

AC:

106

ALSPAC

AF:

0.0330

AC:

127

ESP6500AA

AF:

0.0143

AC:

ESP6500EA

AF:

0.0280

AC:

241

ExAC

AF:

0.0552

AC:

6697

Asia WGS

AF:

0.115

AC:

398

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Methylcobalamin deficiency type cblE (2)

Disorders of Intracellular Cobalamin Metabolism (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.89

MutationAssessor

Pathogenic

3.4

PhyloP100

4.4

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-6.1

REVEL

Uncertain

0.48

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Vest4

0.17

MPC

0.31

ClinPred

0.082

GERP RS

5.2

Varity_R

0.58

gMVP

0.72

Mutation Taster

=89/11

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