rs1802059

Variant names:

• chr5-7897206-G-A
• rs1802059
• NM_002454.3:c.1911G>A

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.1911G>A​(p.Ala637Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 1,613,790 control chromosomes in the GnomAD database, including 99,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7789 hom., cov: 32)
  • Exomes 𝑓: 0.35 (92166 hom.)
• Consequence: MTRR NM_002454.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.55
• Publications: 33 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 (BayesDel_noAF=-0.76).
• BP6: Variant 5-7897206-G-A is Benign according to our data. Variant chr5-7897206-G-A is described in ClinVar as Benign. ClinVar VariationId is 138302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.366 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.1911G>A	p.Ala637Ala	synonymous	Exon 14 of 15	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.1911G>A	p.Ala637Ala	synonymous	Exon 14 of 15	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.1911G>A	p.Ala637Ala	synonymous	Exon 14 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.1911G>A	p.Ala637Ala	synonymous	Exon 14 of 15	ENSP00000402510.2	Q9UBK8-2
	MTRR	ENST00000264668.6	TSL:1	c.1992G>A	p.Ala664Ala	synonymous	Exon 14 of 15	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000513439.5	TSL:1	n.*1618G>A		non_coding_transcript_exon	Exon 14 of 15	ENSP00000426710.1	D6RF21

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47414 AN: 151894 Hom.: 7774 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.315

GnomAD2 exomes AF: 0.310 AC: 77864 AN: 251334 AF XY: 0.319

Gnomad AFR exome AF: 0.251

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.368

Gnomad EAS exome AF: 0.159

Gnomad FIN exome AF: 0.317

Gnomad NFE exome AF: 0.364

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.350 AC: 511732 AN: 1461778 Hom.: 92166 Cov.: 54 AF XY: 0.352 AC XY: 255796 AN XY: 727186

African (AFR) AF: 0.258 AC: 8624 AN: 33480

American (AMR) AF: 0.175 AC: 7821 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 9543 AN: 26130

East Asian (EAS) AF: 0.124 AC: 4921 AN: 39696

South Asian (SAS) AF: 0.365 AC: 31482 AN: 86248

European-Finnish (FIN) AF: 0.323 AC: 17278 AN: 53416

Middle Eastern (MID) AF: 0.395 AC: 2277 AN: 5762

European-Non Finnish (NFE) AF: 0.368 AC: 408820 AN: 1111928

Other (OTH) AF: 0.347 AC: 20966 AN: 60394

GnomAD4 genome AF: 0.312 AC: 47460 AN: 152012 Hom.: 7789 Cov.: 32 AF XY: 0.310 AC XY: 23008 AN XY: 74324

African (AFR) AF: 0.254 AC: 10517 AN: 41448

American (AMR) AF: 0.238 AC: 3642 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1291 AN: 3472

East Asian (EAS) AF: 0.151 AC: 784 AN: 5180

South Asian (SAS) AF: 0.380 AC: 1827 AN: 4806

European-Finnish (FIN) AF: 0.328 AC: 3460 AN: 10554

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.365 AC: 24812 AN: 67960

Other (OTH) AF: 0.316 AC: 667 AN: 2110

Alfa AF: 0.342 Hom.: 15831

Bravo AF: 0.300

Asia WGS AF: 0.298 AC: 1035 AN: 3478

EpiCase AF: 0.365

EpiControl AF: 0.369

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Methylcobalamin deficiency type cblE (4)
-	-	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	-0.76
CADD	Benign	0.70
DANN	Benign	0.78
PhyloP100		-1.6
Mutation Taster		=100/0	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: rs1802059; hg19: chr5-7897319; COSMIC: COSV52941525; COSMIC: COSV52941525;