rs2287779

Variant names:

• chr5-7889103-G-A
• rs2287779
• NM_002454.3:c.1155G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002454.3(MTRR):​c.1155G>A​(p.Leu385Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,613,972 control chromosomes in the GnomAD database, including 2,193 homozygotes. In-silico tool predicts 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 (1919 hom.)
• Consequence: MTRR NM_002454.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.54
• Publications: 22 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 5-7889103-G-A is Benign according to our data. Variant chr5-7889103-G-A is described in ClinVar as Benign. ClinVar VariationId is 138292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.54 with no splicing effect.
• 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.1155G>A	p.Leu385Leu	synonymous	Exon 9 of 15	NP_002445.2
	MTRR	NM_001364440.2		c.1155G>A	p.Leu385Leu	synonymous	Exon 9 of 15	NP_001351369.1
	MTRR	NM_001364441.2		c.1155G>A	p.Leu385Leu	synonymous	Exon 9 of 15	NP_001351370.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTRR	ENST00000440940.7	TSL:1 MANE Select	c.1155G>A	p.Leu385Leu	synonymous	Exon 9 of 15	ENSP00000402510.2
	MTRR	ENST00000264668.6	TSL:1	c.1236G>A	p.Leu412Leu	synonymous	Exon 9 of 15	ENSP00000264668.2
	MTRR	ENST00000513439.5	TSL:1	n.*862G>A		non_coding_transcript_exon	Exon 9 of 15	ENSP00000426710.1

Frequencies

GnomAD3 genomes AF: 0.0440 AC: 6696 AN: 152062 Hom.: 273 Cov.: 32

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0875

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.0383

Gnomad FIN AF: 0.0713

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0431

GnomAD2 exomes AF: 0.0612 AC: 15393 AN: 251406 AF XY: 0.0556

Gnomad AFR exome AF: 0.0255

Gnomad AMR exome AF: 0.140

Gnomad ASJ exome AF: 0.0136

Gnomad EAS exome AF: 0.184

Gnomad FIN exome AF: 0.0697

Gnomad NFE exome AF: 0.0332

Gnomad OTH exome AF: 0.0473

GnomAD4 exome AF: 0.0392 AC: 57359 AN: 1461792 Hom.: 1919 Cov.: 31 AF XY: 0.0386 AC XY: 28063 AN XY: 727204

African (AFR) AF: 0.0232 AC: 776 AN: 33480

American (AMR) AF: 0.135 AC: 6038 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 354 AN: 26136

East Asian (EAS) AF: 0.174 AC: 6900 AN: 39698

South Asian (SAS) AF: 0.0344 AC: 2964 AN: 86250

European-Finnish (FIN) AF: 0.0678 AC: 3623 AN: 53402

Middle Eastern (MID) AF: 0.00679 AC: 39 AN: 5742

European-Non Finnish (NFE) AF: 0.0308 AC: 34240 AN: 1111970

Other (OTH) AF: 0.0402 AC: 2425 AN: 60396

GnomAD4 genome AF: 0.0440 AC: 6698 AN: 152180 Hom.: 274 Cov.: 32 AF XY: 0.0469 AC XY: 3491 AN XY: 74386

African (AFR) AF: 0.0244 AC: 1014 AN: 41544

American (AMR) AF: 0.0874 AC: 1337 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.185 AC: 953 AN: 5138

South Asian (SAS) AF: 0.0381 AC: 184 AN: 4824

European-Finnish (FIN) AF: 0.0713 AC: 755 AN: 10588

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

European-Non Finnish (NFE) AF: 0.0334 AC: 2270 AN: 68006

Other (OTH) AF: 0.0417 AC: 88 AN: 2112

Alfa AF: 0.0409 Hom.: 184

Bravo AF: 0.0447

Asia WGS AF: 0.117 AC: 406 AN: 3478

EpiCase AF: 0.0266

EpiControl AF: 0.0279

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)
-	-	1	Methylcobalamin deficiency type cblE (1)
-	-	1	Methylcobalamin deficiency type cblE;C1866558:Neural tube defects, folate-sensitive (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	7.9
DANN	Benign	0.97
PhyloP100		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=90/10	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: rs2287779; hg19: chr5-7889216; COSMIC: COSV99241337; COSMIC: COSV99241337;