rs9282788

chr5-7900519-T-Cchr5-7900519-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002454.3(MTRR):c.*461T>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 0.0163 in 169,972 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (33 hom., cov: 33)
  • Exomes 𝑓: 0.015 (2 hom.)
• Consequence: MTRR NM_002454.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.41

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=-0.8).
• BP6: Variant 5-7900519-T-C is Benign according to our data. Variant chr5-7900519-T-C is described in ClinVar as [Benign]. Clinvar id is 904711.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0165 (2510/152358) while in subpopulation NFE AF= 0.0253 (1718/68030). AF 95% confidence interval is 0.0243. There are 33 homozygotes in gnomad4. There are 1196 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRR	NM_002454.3	c.*461T>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.*461T>C		3_prime_UTR_variant	15/15	1	NM_002454.3	P1

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2509 AN: 152240 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.00730

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0196

GnomAD4 exome AF: 0.0149 AC: 262 AN: 17614 Hom.: 2 Cov.: 0 AF XY: 0.0146 AC XY: 135 AN XY: 9232

Gnomad4 AFR exome AF: 0.00575

Gnomad4 AMR exome AF: 0.0153

Gnomad4 ASJ exome AF: 0.00855

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000829

Gnomad4 FIN exome AF: 0.00763

Gnomad4 NFE exome AF: 0.0214

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0165 AC: 2510 AN: 152358 Hom.: 33 Cov.: 33 AF XY: 0.0161 AC XY: 1196 AN XY: 74512

Gnomad4 AFR AF: 0.00731

Gnomad4 AMR AF: 0.0141

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.0253

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0163 Hom.: 11

Bravo AF: 0.0167

Asia WGS AF: 0.000866 AC: 3 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	-0.80
Cadd	Benign	6.3
Dann	Benign	0.56

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: rs9282788; hg19: chr5-7900632;