chr5-7878863-T-C

Variant names:

• chr5-7878863-T-C
• rs3776465
• NM_002454.3:c.780+541T>C

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+541T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 152,200 control chromosomes in the GnomAD database, including 6,200 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 0.28 (6200 hom., cov: 32)
• Consequence: MTRR NM_002454.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.152
• Publications: 6 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRR	NM_002454.3	c.780+541T>C		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+541T>C		intron_variant	Intron 5 of 14	1	NM_002454.3	ENSP00000402510.2

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42460 AN: 152082 Hom.: 6200 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.268

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

GnomAD4 genome AF: 0.279 AC: 42465 AN: 152200 Hom.: 6200 Cov.: 32 AF XY: 0.279 AC XY: 20746 AN XY: 74416

African (AFR) AF: 0.236 AC: 9815 AN: 41508

American (AMR) AF: 0.226 AC: 3463 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 797 AN: 3470

East Asian (EAS) AF: 0.188 AC: 974 AN: 5184

South Asian (SAS) AF: 0.243 AC: 1175 AN: 4832

European-Finnish (FIN) AF: 0.350 AC: 3709 AN: 10596

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21568 AN: 67986

Other (OTH) AF: 0.265 AC: 559 AN: 2112

Alfa AF: 0.299 Hom.: 1768

Bravo AF: 0.266

Asia WGS AF: 0.175 AC: 610 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.76
DANN	Benign	0.65
PhyloP100		0.15
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: rs3776465; hg19: chr5-7878976;