rs2287780

Variant names:

• chr5-7889191-C-T
• rs2287780
• NM_002454.3:c.1243C>T

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.1243C>T​(p.Arg415Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,613,882 control chromosomes in the GnomAD database, including 2,191 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (274 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1917 hom.)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.404
• Publications: 43 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, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017158389).
• BP6: Variant 5-7889191-C-T is Benign according to our data. Variant chr5-7889191-C-T is described in ClinVar as Benign. ClinVar VariationId is 138293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

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.1243C>T	p.Arg415Cys	missense	Exon 9 of 15	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.1243C>T	p.Arg415Cys	missense	Exon 9 of 15	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.1243C>T	p.Arg415Cys	missense	Exon 9 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.1243C>T	p.Arg415Cys	missense	Exon 9 of 15	ENSP00000402510.2	Q9UBK8-2
	MTRR	ENST00000264668.6	TSL:1	c.1324C>T	p.Arg442Cys	missense	Exon 9 of 15	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000513439.5	TSL:1	n.*950C>T		non_coding_transcript_exon	Exon 9 of 15	ENSP00000426710.1	D6RF21

Frequencies

GnomAD3 genomes AF: 0.0441 AC: 6702 AN: 152066 Hom.: 273 Cov.: 32

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.0877

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.0381

Gnomad FIN AF: 0.0713

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0430

GnomAD2 exomes AF: 0.0613 AC: 15425 AN: 251454 AF XY: 0.0557

Gnomad AFR exome AF: 0.0256

Gnomad AMR exome AF: 0.140

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.184

Gnomad FIN exome AF: 0.0700

Gnomad NFE exome AF: 0.0332

Gnomad OTH exome AF: 0.0472

GnomAD4 exome AF: 0.0393 AC: 57382 AN: 1461698 Hom.: 1917 Cov.: 31 AF XY: 0.0386 AC XY: 28079 AN XY: 727146

African (AFR) AF: 0.0232 AC: 776 AN: 33476

American (AMR) AF: 0.135 AC: 6042 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0139 AC: 362 AN: 26136

East Asian (EAS) AF: 0.173 AC: 6881 AN: 39700

South Asian (SAS) AF: 0.0344 AC: 2969 AN: 86248

European-Finnish (FIN) AF: 0.0679 AC: 3629 AN: 53416

Middle Eastern (MID) AF: 0.00677 AC: 38 AN: 5612

European-Non Finnish (NFE) AF: 0.0308 AC: 34260 AN: 1112004

Other (OTH) AF: 0.0402 AC: 2425 AN: 60382

GnomAD4 genome AF: 0.0441 AC: 6704 AN: 152184 Hom.: 274 Cov.: 32 AF XY: 0.0470 AC XY: 3494 AN XY: 74400

African (AFR) AF: 0.0244 AC: 1014 AN: 41532

American (AMR) AF: 0.0876 AC: 1338 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3472

East Asian (EAS) AF: 0.185 AC: 955 AN: 5154

South Asian (SAS) AF: 0.0379 AC: 183 AN: 4824

European-Finnish (FIN) AF: 0.0713 AC: 756 AN: 10596

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0334 AC: 2271 AN: 68008

Other (OTH) AF: 0.0416 AC: 88 AN: 2114

Alfa AF: 0.0382 Hom.: 747

Bravo AF: 0.0448

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0337 AC: 130

ESP6500AA AF: 0.0268 AC: 118

ESP6500EA AF: 0.0281 AC: 242

ExAC AF: 0.0566 AC: 6870

Asia WGS AF: 0.117 AC: 406 AN: 3478

EpiCase AF: 0.0266

EpiControl AF: 0.0279

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Methylcobalamin deficiency type cblE (2)
-	-	2	not specified (2)
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Benign	0.011
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.40
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.094
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.047	D
Vest4		0.15
MPC		0.088
ClinPred		0.033	T
GERP RS		4.2
Varity_R		0.22
gMVP		0.31
Mutation Taster		=93/7	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: rs2287780; hg19: chr5-7889304; COSMIC: COSV52944362; COSMIC: COSV52944362;