NM_002454.3:c.401+827G>A

Variant names:

• chr5-7876202-G-A
• rs3776467
• NM_002454.3:c.401+827G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002454.3(MTRR):​c.401+827G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 152,162 control chromosomes in the GnomAD database, including 32,654 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.63 (32654 hom., cov: 34)
• Consequence: MTRR NM_002454.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.28
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3	c.401+827G>A		intron_variant	Intron 4 of 14	ENST00000440940.7	NP_002445.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000440940.7	c.401+827G>A		intron_variant	Intron 4 of 14	1	NM_002454.3	ENSP00000402510.2

Frequencies

GnomAD3 genomes AF: 0.635 AC: 96508 AN: 152044 Hom.: 32659 Cov.: 34

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.798

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.480

Gnomad SAS AF: 0.699

Gnomad FIN AF: 0.819

Gnomad MID AF: 0.713

Gnomad NFE AF: 0.760

Gnomad OTH AF: 0.630

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.634 AC: 96529 AN: 152162 Hom.: 32654 Cov.: 34 AF XY: 0.638 AC XY: 47493 AN XY: 74394

African (AFR) AF: 0.412 AC: 17075 AN: 41488

American (AMR) AF: 0.564 AC: 8612 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 2373 AN: 3472

East Asian (EAS) AF: 0.481 AC: 2484 AN: 5162

South Asian (SAS) AF: 0.699 AC: 3371 AN: 4826

European-Finnish (FIN) AF: 0.819 AC: 8687 AN: 10608

Middle Eastern (MID) AF: 0.719 AC: 210 AN: 292

European-Non Finnish (NFE) AF: 0.760 AC: 51667 AN: 68008

Other (OTH) AF: 0.626 AC: 1322 AN: 2112

Alfa AF: 0.695 Hom.: 35826

Bravo AF: 0.600

Asia WGS AF: 0.564 AC: 1965 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0010
DANN	Benign	0.63
PhyloP100		-2.3
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: rs3776467; hg19: chr5-7876315;