Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_002454.3(MTRR):c.1536C>T(p.Ser512Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,614,144 control chromosomes in the GnomAD database, including 366 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 34 hom., cov: 33)

Exomes 𝑓: 0.020 ( 332 hom. )

Consequence

MTRR
NM_002454.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.367

Publications

7 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 5-7892892-C-T is Benign according to our data. Variant chr5-7892892-C-T is described in ClinVar as Benign. ClinVar VariationId is 138297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.367 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0176 (2674/152314) while in subpopulation NFE AF = 0.0253 (1720/68024). AF 95% confidence interval is 0.0243. There are 34 homozygotes in GnomAd4. There are 1261 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AR gene

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.1536C>T	p.Ser512Ser	synonymous	Exon 11 of 15	NP_002445.2
MTRR	NM_001364440.2		c.1536C>T	p.Ser512Ser	synonymous	Exon 11 of 15	NP_001351369.1
MTRR	NM_001364441.2		c.1536C>T	p.Ser512Ser	synonymous	Exon 11 of 15	NP_001351370.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTRR	ENST00000440940.7	TSL:1 MANE Select	c.1536C>T	p.Ser512Ser	synonymous	Exon 11 of 15	ENSP00000402510.2
MTRR	ENST00000264668.6	TSL:1	c.1617C>T	p.Ser539Ser	synonymous	Exon 11 of 15	ENSP00000264668.2
MTRR	ENST00000513439.5	TSL:1	n.*1243C>T		non_coding_transcript_exon	Exon 11 of 15	ENSP00000426710.1

Frequencies

GnomAD3 genomes

AF:

0.0176

AC:

2672

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0143

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0121

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0253

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.0157

AC:

3949

AN:

251208

AF XY:

0.0153

show subpopulations

Gnomad AFR exome

AF:

0.0124

Gnomad AMR exome

AF:

0.0161

Gnomad ASJ exome

AF:

0.0118

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0119

Gnomad NFE exome

AF:

0.0230

Gnomad OTH exome

AF:

0.0205

GnomAD4 exome

AF:

0.0205

AC:

29913

AN:

1461830

Hom.:

332

Cov.:

AF XY:

0.0200

AC XY:

14515

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0110

AC:

368

AN:

33480

American (AMR)

AF:

0.0158

AC:

706

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

292

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39696

South Asian (SAS)

AF:

0.00264

AC:

228

AN:

86258

European-Finnish (FIN)

AF:

0.0125

AC:

670

AN:

53418

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0238

AC:

26491

AN:

1111972

Other (OTH)

AF:

0.0188

AC:

1133

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

1622

3245

4867

6490

8112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

940

1880

2820

3760

4700

<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:

0.0176

AC:

2674

AN:

152314

Hom.:

Cov.:

AF XY:

0.0169

AC XY:

1261

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0111

AC:

462

AN:

41576

American (AMR)

AF:

0.0143

AC:

218

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00332

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0121

AC:

129

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0253

AC:

1720

AN:

68024

Other (OTH)

AF:

0.0199

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

135

269

404

538

673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0208

Hom.:

Bravo

AF:

0.0179

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0220

EpiControl

AF:

0.0182

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)

not provided (2)

Disorders of Intracellular Cobalamin Metabolism (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

5.4

(source)

DANN

Benign

0.46

PhyloP100

-0.37

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs34172797

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over