rs9282787

Variant names:

• chr5-7900485-T-C
• rs9282787
• NM_002454.3:c.*427T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.357
• Publications: 12 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 354369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3	c.*427T>C		3_prime_UTR_variant	Exon 15 of 15	ENST00000440940.7	NP_002445.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000440940.7	c.*427T>C		3_prime_UTR_variant	Exon 15 of 15	1	NM_002454.3	ENSP00000402510.2

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

African (AFR) AF: 0.119 AC: 117 AN: 986

American (AMR) AF: 0.0956 AC: 343 AN: 3586

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 188 AN: 962

East Asian (EAS) AF: 0.00106 AC: 3 AN: 2842

South Asian (SAS) AF: 0.107 AC: 638 AN: 5954

European-Finnish (FIN) AF: 0.225 AC: 500 AN: 2218

Middle Eastern (MID) AF: 0.122 AC: 18 AN: 148

European-Non Finnish (NFE) AF: 0.234 AC: 6641 AN: 28382

Other (OTH) AF: 0.222 AC: 541 AN: 2440

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

African (AFR) AF: 0.101 AC: 4182 AN: 41556

American (AMR) AF: 0.111 AC: 1694 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 646 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5182

South Asian (SAS) AF: 0.0884 AC: 427 AN: 4828

European-Finnish (FIN) AF: 0.193 AC: 2040 AN: 10584

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13892 AN: 68022

Other (OTH) AF: 0.126 AC: 266 AN: 2116

Alfa AF: 0.180 Hom.: 956

Bravo AF: 0.146

Asia WGS AF: 0.0490 AC: 169 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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	-0.87
CADD	Benign	3.5
DANN	Benign	0.79
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9282787; hg19: chr5-7900598;