rs9282788

Variant names:

• chr5-7900519-T-C
• rs9282788
• NM_002454.3:c.*461T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-7900519-T-C
• chr5-7900519-T-G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3	c.*461T>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.*461T>C		3_prime_UTR_variant	Exon 15 of 15	1	NM_002454.3	ENSP00000402510.2

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

African (AFR) AF: 0.00575 AC: 1 AN: 174

American (AMR) AF: 0.0153 AC: 45 AN: 2944

Ashkenazi Jewish (ASJ) AF: 0.00855 AC: 2 AN: 234

East Asian (EAS) AF: 0.00 AC: 0 AN: 1294

South Asian (SAS) AF: 0.000829 AC: 2 AN: 2412

European-Finnish (FIN) AF: 0.00763 AC: 6 AN: 786

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 22

European-Non Finnish (NFE) AF: 0.0214 AC: 193 AN: 9036

Other (OTH) AF: 0.0183 AC: 13 AN: 712

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

African (AFR) AF: 0.00731 AC: 304 AN: 41602

American (AMR) AF: 0.0141 AC: 216 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4822

European-Finnish (FIN) AF: 0.0121 AC: 128 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0253 AC: 1718 AN: 68030

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.3
DANN	Benign	0.56
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism

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: rs9282788; hg19: chr5-7900632;