rs41283145

Variant names:

• chr5-7892824-A-G
• rs41283145
• NM_002454.3:c.1468A>G
• MTRR p.Thr490Ala

Your query was ambiguous. Multiple possible variants found:

• chr5-7892824-A-G
• chr5-7892824-A-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 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:8
• Conservation: PhyloP100: 7.06
• Publications: 5 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_002454.3
• 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 Benign/Likely_benign. ClinVar VariationId is 439918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002454.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTRR	NM_002454.3	MANE Select	c.1468A>G	p.Thr490Ala	missense	Exon 11 of 15	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.1468A>G	p.Thr490Ala	missense	Exon 11 of 15	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.1468A>G	p.Thr490Ala	missense	Exon 11 of 15	NP_001351370.1	Q9UBK8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTRR	ENST00000440940.7	TSL:1 MANE Select	c.1468A>G	p.Thr490Ala	missense	Exon 11 of 15	ENSP00000402510.2	Q9UBK8-2
	MTRR	ENST00000264668.6	TSL:1	c.1549A>G	p.Thr517Ala	missense	Exon 11 of 15	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000513439.5	TSL:1	n.*1175A>G		non_coding_transcript_exon	Exon 11 of 15	ENSP00000426710.1	D6RF21

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

GnomAD2 exomes AF: 0.00448 AC: 1126 AN: 251462 AF XY: 0.00445

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 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

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.000648 AC: 29 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000754 AC: 65 AN: 86258

European-Finnish (FIN) AF: 0.0155 AC: 827 AN: 53418

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00484 AC: 5379 AN: 1112010

Other (OTH) AF: 0.00371 AC: 224 AN: 60396

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

African (AFR) AF: 0.000770 AC: 32 AN: 41584

American (AMR) AF: 0.000785 AC: 12 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

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

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.0182 AC: 193 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00475 AC: 323 AN: 68024

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00411 Hom.: 23

Bravo AF: 0.00259

EpiCase AF: 0.00382

EpiControl AF: 0.00356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)
-	-	1	Methylcobalamin deficiency type cblE (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.1
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.87
Mutation Taster		=17/83	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41283145;

hg19: chr5-7892937;

COSMIC: COSV52944373;

COSMIC: COSV52944373;