NM_002454.3:c.1049A>G

Variant names:

• chr5-7885846-A-G
• rs162036
• NM_002454.3:c.1049A>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.1049A>G​(p.Lys350Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,613,752 control chromosomes in the GnomAD database, including 20,669 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4532 hom., cov: 31)
  • Exomes 𝑓: 0.13 (16137 hom.)
• Consequence: MTRR NM_002454.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:8
• Conservation: PhyloP100: 1.22
• Publications: 81 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=0.0026747882).
• BP6: Variant 5-7885846-A-G is Benign according to our data. Variant chr5-7885846-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.1049A>G	p.Lys350Arg	missense	Exon 7 of 15	NP_002445.2	Q9UBK8-2
	MTRR	NM_001364440.2		c.1049A>G	p.Lys350Arg	missense	Exon 7 of 15	NP_001351369.1	Q9UBK8-2
	MTRR	NM_001364441.2		c.1049A>G	p.Lys350Arg	missense	Exon 7 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.1049A>G	p.Lys350Arg	missense	Exon 7 of 15	ENSP00000402510.2	Q9UBK8-2
	MTRR	ENST00000264668.6	TSL:1	c.1130A>G	p.Lys377Arg	missense	Exon 7 of 15	ENSP00000264668.2	Q9UBK8-1
	MTRR	ENST00000513439.5	TSL:1	n.*756A>G		non_coding_transcript_exon	Exon 7 of 15	ENSP00000426710.1	D6RF21

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31298 AN: 151904 Hom.: 4518 Cov.: 31

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0682

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.176 AC: 44240 AN: 251438 AF XY: 0.163

Gnomad AFR exome AF: 0.394

Gnomad AMR exome AF: 0.367

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.183

Gnomad FIN exome AF: 0.0752

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.133 AC: 193961 AN: 1461728 Hom.: 16137 Cov.: 36 AF XY: 0.131 AC XY: 95378 AN XY: 727168

African (AFR) AF: 0.393 AC: 13139 AN: 33474

American (AMR) AF: 0.357 AC: 15945 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 4582 AN: 26134

East Asian (EAS) AF: 0.166 AC: 6593 AN: 39698

South Asian (SAS) AF: 0.145 AC: 12548 AN: 86242

European-Finnish (FIN) AF: 0.0740 AC: 3954 AN: 53398

Middle Eastern (MID) AF: 0.158 AC: 909 AN: 5768

European-Non Finnish (NFE) AF: 0.115 AC: 127319 AN: 1111914

Other (OTH) AF: 0.149 AC: 8972 AN: 60380

GnomAD4 genome AF: 0.206 AC: 31363 AN: 152024 Hom.: 4532 Cov.: 31 AF XY: 0.204 AC XY: 15165 AN XY: 74302

African (AFR) AF: 0.381 AC: 15776 AN: 41394

American (AMR) AF: 0.296 AC: 4525 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 606 AN: 3470

East Asian (EAS) AF: 0.173 AC: 896 AN: 5172

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

European-Finnish (FIN) AF: 0.0682 AC: 723 AN: 10598

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

European-Non Finnish (NFE) AF: 0.112 AC: 7644 AN: 67986

Other (OTH) AF: 0.200 AC: 422 AN: 2112

Alfa AF: 0.148 Hom.: 9474

Bravo AF: 0.233

TwinsUK AF: 0.118 AC: 438

ALSPAC AF: 0.115 AC: 443

ESP6500AA AF: 0.377 AC: 1662

ESP6500EA AF: 0.118 AC: 1019

ExAC AF: 0.171 AC: 20761

Asia WGS AF: 0.158 AC: 553 AN: 3478

EpiCase AF: 0.121

EpiControl AF: 0.124

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	-	Gastrointestinal stromal tumor (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.5
DANN	Benign	0.97
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.74
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.11
Sift	Benign	0.24	T
Sift4G	Benign	0.14	T
Vest4		0.024
MPC		0.050
ClinPred		0.0093	T
GERP RS		-2.2
Varity_R		0.099
gMVP		0.35
Mutation Taster		=97/3	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: rs162036; hg19: chr5-7885959; COSMIC: COSV52941474; COSMIC: COSV52941474;