dbSNP rs35890938: MTRR:p.Val488Val (chr5-7892820-A-G) – ACMG Classification: Benign (-21 pts)

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.1464A>G(p.Val488Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,614,200 control chromosomes in the GnomAD database, including 364 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 33 hom., cov: 33)

Exomes 𝑓: 0.020 ( 331 hom. )

Consequence

MTRR
NM_002454.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.248

Publications

6 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

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=-0.66).

BP6

Variant 5-7892820-A-G is Benign according to our data. Variant chr5-7892820-A-G is described in ClinVar as Benign. ClinVar VariationId is 138296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.248 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0165 (2510/152316) while in subpopulation NFE AF = 0.0253 (1718/68018). AF 95% confidence interval is 0.0243. There are 33 homozygotes in GnomAd4. There are 1195 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 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	UniProt
MTRR	NM_002454.3	MANE Select	c.1464A>G	p.Val488Val	synonymous	Exon 11 of 15	NP_002445.2	Q9UBK8-2
MTRR	NM_001364440.2		c.1464A>G	p.Val488Val	synonymous	Exon 11 of 15	NP_001351369.1	Q9UBK8-2
MTRR	NM_001364441.2		c.1464A>G	p.Val488Val	synonymous	Exon 11 of 15	NP_001351370.1	Q9UBK8-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MTRR	ENST00000440940.7	TSL:1 MANE Select	c.1464A>G	p.Val488Val	synonymous	Exon 11 of 15	ENSP00000402510.2	Q9UBK8-2
MTRR	ENST00000264668.6	TSL:1	c.1545A>G	p.Val515Val	synonymous	Exon 11 of 15	ENSP00000264668.2	Q9UBK8-1
MTRR	ENST00000513439.5	TSL:1	n.*1171A>G		non_coding_transcript_exon	Exon 11 of 15	ENSP00000426710.1	D6RF21

Frequencies

GnomAD3 genomes

AF:

0.0165

AC:

2509

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00733

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0140

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0253

Gnomad OTH

AF:

0.0196

GnomAD2 exomes

AF:

0.0154

AC:

3867

AN:

251462

AF XY:

0.0150

show subpopulations

Gnomad AFR exome

AF:

0.00769

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:

0.0229

Gnomad OTH exome

AF:

0.0205

GnomAD4 exome

AF:

0.0203

AC:

29668

AN:

1461884

Hom.:

331

Cov.:

AF XY:

0.0198

AC XY:

14416

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00672

AC:

225

AN:

33480

American (AMR)

AF:

0.0157

AC:

702

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

292

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39696

South Asian (SAS)

AF:

0.00262

AC:

226

AN:

86258

European-Finnish (FIN)

AF:

0.0125

AC:

670

AN:

53420

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0237

AC:

26403

AN:

1112006

Other (OTH)

AF:

0.0186

AC:

1126

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

1736

3472

5209

6945

8681

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

934

1868

2802

3736

4670

<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:

0.0165

AC:

2510

AN:

152316

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

1195

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00733

AC:

305

AN:

41582

American (AMR)

AF:

0.0140

AC:

214

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00331

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0122

AC:

129

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0253

AC:

1718

AN:

68018

Other (OTH)

AF:

0.0194

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

126

252

379

505

631

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0204

Hom.:

Bravo

AF:

0.0167

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0220

EpiControl

AF:

0.0182

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Methylcobalamin deficiency type cblE (2)

not provided (2)

not specified (2)

Disorders of Intracellular Cobalamin Metabolism (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

5.8

(source)

DANN

Benign

0.68

PhyloP100

-0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=96/4

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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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