NM_002454.3:c.537T>C

Variant names:

• chr5-7878079-T-C
• rs161870
• NM_002454.3:c.537T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002454.3(MTRR):​c.537T>C​(p.Leu179Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,613,688 control chromosomes in the GnomAD database, including 20,659 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L179L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.21 (4532 hom., cov: 31)
  • Exomes 𝑓: 0.13 (16127 hom.)
• Consequence: MTRR NM_002454.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.79
• Publications: 23 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.006).
• BP6: Variant 5-7878079-T-C is Benign according to our data. Variant chr5-7878079-T-C is described in ClinVar as Benign. ClinVar VariationId is 138305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.376 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.537T>C	p.Leu179Leu	synonymous	Exon 5 of 15	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.537T>C	p.Leu179Leu	synonymous	Exon 5 of 15	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.537T>C	p.Leu179Leu	synonymous	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.537T>C	p.Leu179Leu	synonymous	Exon 5 of 15	ENSP00000402510.2	Q9UBK8-2
	MTRR	ENST00000264668.6	TSL:1	c.618T>C	p.Leu206Leu	synonymous	Exon 5 of 15	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000513439.5	TSL:1	n.*244T>C		non_coding_transcript_exon	Exon 5 of 15	ENSP00000426710.1	D6RF21

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31265 AN: 151714 Hom.: 4518 Cov.: 31

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0683

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.199

GnomAD2 exomes AF: 0.176 AC: 44201 AN: 251326 AF XY: 0.163

Gnomad AFR exome AF: 0.394

Gnomad AMR exome AF: 0.368

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.184

Gnomad FIN exome AF: 0.0751

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.133 AC: 193954 AN: 1461856 Hom.: 16127 Cov.: 35 AF XY: 0.131 AC XY: 95368 AN XY: 727220

African (AFR) AF: 0.392 AC: 13136 AN: 33478

American (AMR) AF: 0.357 AC: 15950 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 4582 AN: 26136

East Asian (EAS) AF: 0.166 AC: 6596 AN: 39700

South Asian (SAS) AF: 0.145 AC: 12507 AN: 86258

European-Finnish (FIN) AF: 0.0740 AC: 3953 AN: 53420

Middle Eastern (MID) AF: 0.158 AC: 910 AN: 5768

European-Non Finnish (NFE) AF: 0.115 AC: 127352 AN: 1111984

Other (OTH) AF: 0.148 AC: 8968 AN: 60394

GnomAD4 genome AF: 0.206 AC: 31329 AN: 151832 Hom.: 4532 Cov.: 31 AF XY: 0.204 AC XY: 15159 AN XY: 74198

African (AFR) AF: 0.381 AC: 15769 AN: 41342

American (AMR) AF: 0.296 AC: 4510 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 605 AN: 3466

East Asian (EAS) AF: 0.173 AC: 885 AN: 5118

South Asian (SAS) AF: 0.142 AC: 682 AN: 4810

European-Finnish (FIN) AF: 0.0683 AC: 721 AN: 10558

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7646 AN: 67970

Other (OTH) AF: 0.200 AC: 422 AN: 2106

Alfa AF: 0.154 Hom.: 1255

Bravo AF: 0.233

Asia WGS AF: 0.158 AC: 551 AN: 3478

EpiCase AF: 0.121

EpiControl AF: 0.125

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Methylcobalamin deficiency type cblE (4)
-	-	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
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.14
DANN	Benign	0.45
PhyloP100		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs161870; hg19: chr5-7878192;