rs9282787

chr5-7900485-T-C

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.*427T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 199,780 control chromosomes in the GnomAD database, including 2,983 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2069 hom., cov: 32)
  • Exomes 𝑓: 0.19 (914 hom.)
• Consequence: MTRR NM_002454.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.357

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=-0.87).
• BP6: Variant 5-7900485-T-C is Benign according to our data. Variant chr5-7900485-T-C is described in ClinVar as [Benign]. Clinvar id is 354369.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRR	NM_002454.3	c.*427T>C		3_prime_UTR_variant	15/15	ENST00000440940.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRR	ENST00000440940.7	c.*427T>C		3_prime_UTR_variant	15/15	1	NM_002454.3	P1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23389 AN: 152144 Hom.: 2064 Cov.: 32

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0877

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.127

GnomAD4 exome AF: 0.189 AC: 8989 AN: 47518 Hom.: 914 Cov.: 0 AF XY: 0.183 AC XY: 4475 AN XY: 24490

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.0956

Gnomad4 ASJ exome AF: 0.195

Gnomad4 EAS exome AF: 0.00106

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.225

Gnomad4 NFE exome AF: 0.234

Gnomad4 OTH exome AF: 0.222

GnomAD4 genome AF: 0.154 AC: 23414 AN: 152262 Hom.: 2069 Cov.: 32 AF XY: 0.151 AC XY: 11214 AN XY: 74450

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.186

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0884

Gnomad4 FIN AF: 0.193

Gnomad4 NFE AF: 0.204

Gnomad4 OTH AF: 0.126

Alfa AF: 0.181 Hom.: 584

Bravo AF: 0.146

Asia WGS AF: 0.0490 AC: 169 AN: 3478

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	-0.87
Cadd	Benign	3.5
Dann	Benign	0.79

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: rs9282787; hg19: chr5-7900598;