rs2303080

Variant names:

• chr5-7878311-T-A
• rs2303080
• NM_002454.3:c.769T>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.769T>A​(p.Ser257Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0333 in 1,613,958 control chromosomes in the GnomAD database, including 1,260 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (136 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1124 hom.)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.75
• Publications: 35 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=0.0014932454).
• BP6: Variant 5-7878311-T-A is Benign according to our data. Variant chr5-7878311-T-A is described in ClinVar as Benign. ClinVar VariationId is 138306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 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.769T>A	p.Ser257Thr	missense	Exon 5 of 15	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.769T>A	p.Ser257Thr	missense	Exon 5 of 15	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.769T>A	p.Ser257Thr	missense	Exon 5 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.769T>A	p.Ser257Thr	missense	Exon 5 of 15	ENSP00000402510.2	Q9UBK8-2
	MTRR	ENST00000264668.6	TSL:1	c.850T>A	p.Ser284Thr	missense	Exon 5 of 15	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000513439.5	TSL:1	n.*476T>A		non_coding_transcript_exon	Exon 5 of 15	ENSP00000426710.1	D6RF21

Frequencies

GnomAD3 genomes AF: 0.0313 AC: 4760 AN: 152060 Hom.: 136 Cov.: 32

Gnomad AFR AF: 0.00734

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0441

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0210

Gnomad FIN AF: 0.0702

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0283

GnomAD2 exomes AF: 0.0432 AC: 10862 AN: 251340 AF XY: 0.0403

Gnomad AFR exome AF: 0.00691

Gnomad AMR exome AF: 0.0772

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.110

Gnomad FIN exome AF: 0.0694

Gnomad NFE exome AF: 0.0327

Gnomad OTH exome AF: 0.0354

GnomAD4 exome AF: 0.0335 AC: 49017 AN: 1461780 Hom.: 1124 Cov.: 34 AF XY: 0.0329 AC XY: 23899 AN XY: 727182

African (AFR) AF: 0.00517 AC: 173 AN: 33478

American (AMR) AF: 0.0751 AC: 3361 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 305 AN: 26136

East Asian (EAS) AF: 0.108 AC: 4295 AN: 39700

South Asian (SAS) AF: 0.0172 AC: 1480 AN: 86256

European-Finnish (FIN) AF: 0.0674 AC: 3599 AN: 53420

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.0305 AC: 33921 AN: 1111904

Other (OTH) AF: 0.0307 AC: 1855 AN: 60394

GnomAD4 genome AF: 0.0313 AC: 4758 AN: 152178 Hom.: 136 Cov.: 32 AF XY: 0.0331 AC XY: 2460 AN XY: 74396

African (AFR) AF: 0.00735 AC: 305 AN: 41518

American (AMR) AF: 0.0440 AC: 673 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.109 AC: 565 AN: 5172

South Asian (SAS) AF: 0.0212 AC: 102 AN: 4812

European-Finnish (FIN) AF: 0.0702 AC: 743 AN: 10584

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

European-Non Finnish (NFE) AF: 0.0327 AC: 2222 AN: 68010

Other (OTH) AF: 0.0275 AC: 58 AN: 2108

Alfa AF: 0.0322 Hom.: 85

Bravo AF: 0.0289

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0327 AC: 126

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.0280 AC: 241

ExAC AF: 0.0405 AC: 4920

Asia WGS AF: 0.0640 AC: 224 AN: 3478

EpiCase AF: 0.0261

EpiControl AF: 0.0276

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.0040
DANN	Benign	0.24
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		-2.7
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.038
Sift	Benign	0.51	T
Sift4G	Benign	0.59	T
Vest4		0.028
MPC		0.044
ClinPred		0.0043	T
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.30
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2303080; hg19: chr5-7878424; COSMIC: COSV108061613; COSMIC: COSV108061613;