rs41283145

chr5-7892824-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002454.3(MTRR):c.1468A>G(p.Thr490Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00444 in 1,614,222 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (22 hom.)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.06

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01696533).
• BP6: Variant 5-7892824-A-G is Benign according to our data. Variant chr5-7892824-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 439918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7892824-A-G is described in Lovd as [Likely_benign]. Variant chr5-7892824-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00389 (592/152336) while in subpopulation NFE AF= 0.00475 (323/68024). AF 95% confidence interval is 0.00432. There are 2 homozygotes in gnomad4. There are 349 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRR	NM_002454.3	c.1468A>G	p.Thr490Ala	missense_variant	11/15	ENST00000440940.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRR	ENST00000440940.7	c.1468A>G	p.Thr490Ala	missense_variant	11/15	1	NM_002454.3	P1

Frequencies

GnomAD3 genomes AF: 0.00389 AC: 592 AN: 152218 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00448 AC: 1126 AN: 251462 Hom.: 4 AF XY: 0.00445 AC XY: 605 AN XY: 135898

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.0156

Gnomad NFE exome AF: 0.00615

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00450 AC: 6572 AN: 1461886 Hom.: 22 Cov.: 31 AF XY: 0.00428 AC XY: 3112 AN XY: 727242

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000754

Gnomad4 FIN exome AF: 0.0155

Gnomad4 NFE exome AF: 0.00484

Gnomad4 OTH exome AF: 0.00371

GnomAD4 genome AF: 0.00389 AC: 592 AN: 152336 Hom.: 2 Cov.: 33 AF XY: 0.00469 AC XY: 349 AN XY: 74482

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0182

Gnomad4 NFE AF: 0.00475

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00410 Hom.: 2

Bravo AF: 0.00259

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00464 AC: 563

EpiCase AF: 0.00382

EpiControl AF: 0.00356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MTRR: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Disorders of Intracellular Cobalamin Metabolism Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Methylcobalamin deficiency type cblE Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.017	T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0060	D;D
Vest4		0.90
MVP		0.75
MPC		0.22
ClinPred		0.044	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs41283145; hg19: chr5-7892937; COSMIC: COSV52944373; COSMIC: COSV52944373;