rs9332

Variant names:

• chr5-7900599-G-A
• rs9332
• NM_002454.3:c.*541G>A

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.*541G>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 0.205 in 152,788 control chromosomes in the GnomAD database, including 4,514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4511 hom., cov: 33)
  • Exomes 𝑓: 0.073 (3 hom.)
• Consequence: MTRR NM_002454.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.157
• Publications: 21 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=-0.77).
• BP6: Variant 5-7900599-G-A is Benign according to our data. Variant chr5-7900599-G-A is described in ClinVar as Benign. ClinVar VariationId is 354370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3	c.*541G>A		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.*541G>A		3_prime_UTR_variant	Exon 15 of 15	1	NM_002454.3	ENSP00000402510.2

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31185 AN: 151906 Hom.: 4496 Cov.: 33

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0690

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.198

GnomAD4 exome AF: 0.0733 AC: 56 AN: 764 Hom.: 3 Cov.: 0 AF XY: 0.0783 AC XY: 34 AN XY: 434

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 0.143 AC: 6 AN: 42

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 0.143 AC: 2 AN: 14

European-Finnish (FIN) AF: 0.0516 AC: 22 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0871 AC: 23 AN: 264

Other (OTH) AF: 0.167 AC: 2 AN: 12

GnomAD4 genome AF: 0.206 AC: 31251 AN: 152024 Hom.: 4511 Cov.: 33 AF XY: 0.203 AC XY: 15107 AN XY: 74290

African (AFR) AF: 0.381 AC: 15807 AN: 41474

American (AMR) AF: 0.296 AC: 4517 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 606 AN: 3470

East Asian (EAS) AF: 0.147 AC: 759 AN: 5162

South Asian (SAS) AF: 0.141 AC: 680 AN: 4808

European-Finnish (FIN) AF: 0.0690 AC: 728 AN: 10556

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7643 AN: 67976

Other (OTH) AF: 0.200 AC: 422 AN: 2114

Alfa AF: 0.147 Hom.: 2096

Bravo AF: 0.232

Asia WGS AF: 0.152 AC: 529 AN: 3474

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	-0.77
CADD	Benign	4.0
DANN	Benign	0.71
PhyloP100		0.16
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: rs9332; hg19: chr5-7900712; COSMIC: COSV105099451; COSMIC: COSV105099451;