chr5-7878881-T-A

Variant names:

• chr5-7878881-T-A
• rs3776464
• NM_002454.3:c.780+559T>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.780+559T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0441 in 152,312 control chromosomes in the GnomAD database, including 276 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 0.044 (276 hom., cov: 31)
• Consequence: MTRR NM_002454.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.106
• Publications: 4 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3	c.780+559T>A		intron_variant	Intron 5 of 14	ENST00000440940.7	NP_002445.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000440940.7	c.780+559T>A		intron_variant	Intron 5 of 14	1	NM_002454.3	ENSP00000402510.2

Frequencies

GnomAD3 genomes AF: 0.0441 AC: 6714 AN: 152194 Hom.: 275 Cov.: 31

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0878

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.0381

Gnomad FIN AF: 0.0712

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0430

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

GnomAD4 genome AF: 0.0441 AC: 6716 AN: 152312 Hom.: 276 Cov.: 31 AF XY: 0.0470 AC XY: 3504 AN XY: 74482

African (AFR) AF: 0.0244 AC: 1016 AN: 41582

American (AMR) AF: 0.0877 AC: 1342 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3466

East Asian (EAS) AF: 0.186 AC: 961 AN: 5178

South Asian (SAS) AF: 0.0379 AC: 183 AN: 4826

European-Finnish (FIN) AF: 0.0712 AC: 756 AN: 10622

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0334 AC: 2273 AN: 68020

Other (OTH) AF: 0.0416 AC: 88 AN: 2114

Alfa AF: 0.0255 Hom.: 21

Bravo AF: 0.0448

Asia WGS AF: 0.117 AC: 405 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.1
DANN	Benign	0.73
PhyloP100		-0.11
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: rs3776464; hg19: chr5-7878994;