Genetic Variant MTRR:c.1677-466C>T (chr5-7896398-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002454.3(MTRR):c.1677-466C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 205,040 control chromosomes in the GnomAD database, including 37,251 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.58 ( 26190 hom., cov: 33)

Exomes 𝑓: 0.63 ( 11061 hom. )

Consequence

MTRR
NM_002454.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0470

Publications

18 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3 link	c.1677-466C>T		intron_variant	Intron 12 of 14	ENST00000440940.7	NP_002445.2	Q9UBK8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000440940.7 link	c.1677-466C>T		intron_variant	Intron 12 of 14	1	NM_002454.3	ENSP00000402510.2		Q9UBK8-2

Frequencies

GnomAD3 genomes

AF:

0.577

AC:

87634

AN:

151956

Hom.:

26182

Cov.:

show subpopulations

Gnomad AFR

AF:

0.488

Gnomad AMI

AF:

0.700

Gnomad AMR

AF:

0.453

Gnomad ASJ

AF:

0.589

Gnomad EAS

AF:

0.338

Gnomad SAS

AF:

0.619

Gnomad FIN

AF:

0.667

Gnomad MID

AF:

0.636

Gnomad NFE

AF:

0.658

Gnomad OTH

AF:

0.565

GnomAD4 exome

AF:

0.633

AC:

33536

AN:

52966

Hom.:

11061

Cov.:

AF XY:

0.632

AC XY:

17332

AN XY:

27408

show subpopulations

African (AFR)

AF:

0.542

AC:

399

AN:

736

American (AMR)

AF:

0.381

AC:

1365

AN:

3580

Ashkenazi Jewish (ASJ)

AF:

0.599

AC:

663

AN:

1106

East Asian (EAS)

AF:

0.334

AC:

848

AN:

2536

South Asian (SAS)

AF:

0.641

AC:

4390

AN:

6844

European-Finnish (FIN)

AF:

0.692

AC:

1445

AN:

2088

Middle Eastern (MID)

AF:

0.678

AC:

118

AN:

174

European-Non Finnish (NFE)

AF:

0.680

AC:

22440

AN:

32996

Other (OTH)

AF:

0.643

AC:

1868

AN:

2906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

Heterozygous variant carriers

554

1108

1662

2216

2770

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.577

AC:

87683

AN:

152074

Hom.:

26190

Cov.:

AF XY:

0.574

AC XY:

42696

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.488

AC:

20230

AN:

41468

American (AMR)

AF:

0.452

AC:

6909

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.589

AC:

2041

AN:

3468

East Asian (EAS)

AF:

0.339

AC:

1750

AN:

5164

South Asian (SAS)

AF:

0.620

AC:

2984

AN:

4816

European-Finnish (FIN)

AF:

0.667

AC:

7044

AN:

10568

Middle Eastern (MID)

AF:

0.636

AC:

187

AN:

294

European-Non Finnish (NFE)

AF:

0.658

AC:

44712

AN:

67996

Other (OTH)

AF:

0.563

AC:

1188

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1829

3659

5488

7318

9147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.619

Hom.:

80361

Bravo

AF:

0.551

Asia WGS

AF:

0.472

AC:

1642

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.34

(source)

DANN

Benign

0.68

PhyloP100

-0.047

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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5-7896398-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over