rs8659

chr5-7900720-T-Achr5-7900720-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.534

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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/exons	MANE	UniProt
MTRR	NM_002454.3	c.*662T>A		3_prime_UTR_variant	15/15	ENST00000440940.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRR	ENST00000440940.7	c.*662T>A		3_prime_UTR_variant	15/15	1	NM_002454.3	P1

Frequencies

GnomAD3 genomes AF: 0.575 AC: 87407 AN: 151992 Hom.: 26078 Cov.: 33

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

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

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Disorders of Intracellular Cobalamin Metabolism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

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

Other links and lift over

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