rs1801394

Variant names:

• chr5-7870860-A-G
• rs1801394
• NM_002454.3:c.66A>G

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.66A>G​(p.Ile22Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 1,613,968 control chromosomes in the GnomAD database, including 229,509 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16800 hom., cov: 34)
  • Exomes 𝑓: 0.53 (212709 hom.)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:11 O:3
• Conservation: PhyloP100: 0.0980
• Publications: 780 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.4935942E-4).
• BP6: Variant 5-7870860-A-G is Benign according to our data. Variant chr5-7870860-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 7029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.553 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTRR	NM_002454.3	MANE Select	c.66A>G	p.Ile22Met	missense	Exon 2 of 15	NP_002445.2
	MTRR	NM_001364440.2		c.66A>G	p.Ile22Met	missense	Exon 2 of 15	NP_001351369.1
	MTRR	NM_001364441.2		c.66A>G	p.Ile22Met	missense	Exon 2 of 15	NP_001351370.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTRR	ENST00000440940.7	TSL:1 MANE Select	c.66A>G	p.Ile22Met	missense	Exon 2 of 15	ENSP00000402510.2
	MTRR	ENST00000264668.6	TSL:1	c.147A>G	p.Ile49Met	missense	Exon 2 of 15	ENSP00000264668.2
	MTRR	ENST00000513439.5	TSL:1	n.66A>G		non_coding_transcript_exon	Exon 2 of 15	ENSP00000426710.1

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68524 AN: 152052 Hom.: 16801 Cov.: 34

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.676

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.529

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.430

GnomAD2 exomes AF: 0.466 AC: 117132 AN: 251460 AF XY: 0.482

Gnomad AFR exome AF: 0.274

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.455

Gnomad EAS exome AF: 0.279

Gnomad FIN exome AF: 0.565

Gnomad NFE exome AF: 0.554

Gnomad OTH exome AF: 0.491

GnomAD4 exome AF: 0.532 AC: 777894 AN: 1461798 Hom.: 212709 Cov.: 50 AF XY: 0.534 AC XY: 387990 AN XY: 727196

African (AFR) AF: 0.275 AC: 9221 AN: 33476

American (AMR) AF: 0.264 AC: 11788 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 11718 AN: 26134

East Asian (EAS) AF: 0.292 AC: 11591 AN: 39696

South Asian (SAS) AF: 0.524 AC: 45222 AN: 86256

European-Finnish (FIN) AF: 0.572 AC: 30549 AN: 53414

Middle Eastern (MID) AF: 0.428 AC: 2469 AN: 5768

European-Non Finnish (NFE) AF: 0.562 AC: 625139 AN: 1111936

Other (OTH) AF: 0.500 AC: 30197 AN: 60394

GnomAD4 genome AF: 0.450 AC: 68539 AN: 152170 Hom.: 16800 Cov.: 34 AF XY: 0.452 AC XY: 33597 AN XY: 74408

African (AFR) AF: 0.281 AC: 11669 AN: 41506

American (AMR) AF: 0.367 AC: 5609 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1583 AN: 3470

East Asian (EAS) AF: 0.283 AC: 1466 AN: 5174

South Asian (SAS) AF: 0.529 AC: 2553 AN: 4824

European-Finnish (FIN) AF: 0.578 AC: 6127 AN: 10596

Middle Eastern (MID) AF: 0.383 AC: 111 AN: 290

European-Non Finnish (NFE) AF: 0.557 AC: 37907 AN: 67996

Other (OTH) AF: 0.426 AC: 899 AN: 2110

Alfa AF: 0.508 Hom.: 91964

Bravo AF: 0.421

TwinsUK AF: 0.553 AC: 2050

ALSPAC AF: 0.565 AC: 2179

ESP6500AA AF: 0.270 AC: 1188

ESP6500EA AF: 0.546 AC: 4696

ExAC AF: 0.473 AC: 57411

Asia WGS AF: 0.387 AC: 1347 AN: 3478

EpiCase AF: 0.529

EpiControl AF: 0.524

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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	-	Gastrointestinal stromal tumor (1)
-	-	1	not provided (1)
-	-	-	Down syndrome, susceptibility to (1)
-	-	-	Methotrexate response (1)
-	-	-	Neural tube defects, folate-sensitive, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.070
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.10	N
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.00045	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.098
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Vest4		0.26
MPC		0.32
ClinPred		0.049	T
GERP RS		0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.37
gMVP		0.77
Mutation Taster		=97/3	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: rs1801394; hg19: chr5-7870973; COSMIC: COSV52943975; COSMIC: COSV52943975;