Genetic Variant MTRR:c.*662T>A (chr5-7900720-T-A) – ACMG Classification: Benign (-20 pts)

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.*662T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 152,572 control chromosomes in the GnomAD database, including 26,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 26086 hom., cov: 33)

Exomes 𝑓: 0.66 ( 104 hom. )

Consequence

MTRR
NM_002454.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.534

Publications

25 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 5-7900720-T-A is Benign according to our data. Variant chr5-7900720-T-A is described in ClinVar as Benign. ClinVar VariationId is 354373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.652 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	Effect	Exon Rank	Protein	UniProt
MTRR	NM_002454.3	MANE Select	c.*662T>A	3_prime_UTR	Exon 15 of 15	NP_002445.2	Q9UBK8-2
MTRR	NM_001364440.2		c.*662T>A	3_prime_UTR	Exon 15 of 15	NP_001351369.1	Q9UBK8-2
MTRR	NM_001364441.2		c.*662T>A	3_prime_UTR	Exon 15 of 15	NP_001351370.1	Q9UBK8-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MTRR	ENST00000440940.7	TSL:1 MANE Select	c.*662T>A	3_prime_UTR	Exon 15 of 15	ENSP00000402510.2	Q9UBK8-2
MTRR	ENST00000264668.6	TSL:1	c.*662T>A	3_prime_UTR	Exon 15 of 15	ENSP00000264668.2	Q9UBK8-1
MTRR	ENST00000869929.1		c.*662T>A	3_prime_UTR	Exon 15 of 15	ENSP00000539988.1

Frequencies

GnomAD3 genomes

AF:

0.575

AC:

87407

AN:

151992

Hom.:

26078

Cov.:

show subpopulations

Gnomad AFR

AF:

0.483

Gnomad AMI

AF:

0.700

Gnomad AMR

AF:

0.452

Gnomad ASJ

AF:

0.589

Gnomad EAS

AF:

0.338

Gnomad SAS

AF:

0.619

Gnomad FIN

AF:

0.666

Gnomad MID

AF:

0.638

Gnomad NFE

AF:

0.658

Gnomad OTH

AF:

0.564

GnomAD4 exome

AF:

0.657

AC:

302

AN:

460

Hom.:

104

Cov.:

AF XY:

0.692

AC XY:

191

AN XY:

276

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.667

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.649

AC:

275

AN:

424

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.818

AC:

AN:

Other (OTH)

AF:

0.750

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.575

AC:

87456

AN:

152112

Hom.:

26086

Cov.:

AF XY:

0.573

AC XY:

42573

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.483

AC:

20032

AN:

41488

American (AMR)

AF:

0.451

AC:

6892

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.589

AC:

2042

AN:

3468

East Asian (EAS)

AF:

0.339

AC:

1756

AN:

5182

South Asian (SAS)

AF:

0.619

AC:

2987

AN:

4822

European-Finnish (FIN)

AF:

0.666

AC:

7027

AN:

10558

Middle Eastern (MID)

AF:

0.634

AC:

185

AN:

292

European-Non Finnish (NFE)

AF:

0.657

AC:

44708

AN:

67998

Other (OTH)

AF:

0.562

AC:

1189

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1840

3679

5519

7358

9198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

744

1488

2232

2976

3720

<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:

0.606

Hom.:

3530

Bravo

AF:

0.550

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Disorders of Intracellular Cobalamin Metabolism (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.69

(source)

DANN

Benign

0.42

PhyloP100

0.53

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

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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