rs8659

Variant summary

Our verdict is Benign. Variant got -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

2

Clinical Significance

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

Conservation

PhyloP100: 0.534
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MTRRNM_002454.3 linkc.*662T>A 3_prime_UTR_variant Exon 15 of 15 ENST00000440940.7 NP_002445.2 Q9UBK8-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MTRRENST00000440940.7 linkc.*662T>A 3_prime_UTR_variant Exon 15 of 15 1 NM_002454.3 ENSP00000402510.2 Q9UBK8-2

Frequencies

GnomAD3 genomes
AF:
0.575
AC:
87407
AN:
151992
Hom.:
26078
Cov.:
33
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.:
0
AF XY:
0.692
AC XY:
191
AN XY:
276
show subpopulations
Gnomad4 AMR exome
AF:
0.667
Gnomad4 SAS exome
AF:
0.500
Gnomad4 FIN exome
AF:
0.649
Gnomad4 NFE exome
AF:
0.818
Gnomad4 OTH exome
AF:
0.750
GnomAD4 genome
AF:
0.575
AC:
87456
AN:
152112
Hom.:
26086
Cov.:
33
AF XY:
0.573
AC XY:
42573
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.483
Gnomad4 AMR
AF:
0.451
Gnomad4 ASJ
AF:
0.589
Gnomad4 EAS
AF:
0.339
Gnomad4 SAS
AF:
0.619
Gnomad4 FIN
AF:
0.666
Gnomad4 NFE
AF:
0.657
Gnomad4 OTH
AF:
0.562
Alfa
AF:
0.606
Hom.:
3530
Bravo
AF:
0.550

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Disorders of Intracellular Cobalamin Metabolism Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
0.69
DANN
Benign
0.42

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs8659; hg19: chr5-7900833; COSMIC: COSV52948174; COSMIC: COSV52948174; API