rs3776455

Positions:

• chr5-7896398-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002454.3(MTRR):​c.1677-466C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 205,040 control chromosomes in the GnomAD database, including 37,251 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 0.58 (26190 hom., cov: 33)
  • Exomes 𝑓: 0.63 (11061 hom.)
• Consequence: MTRR NM_002454.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0470

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTRR	NM_002454.3	c.1677-466C>T		intron_variant		ENST00000440940.7	NP_002445.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000440940.7	c.1677-466C>T		intron_variant		1	NM_002454.3	ENSP00000402510	P1

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87634 AN: 151956 Hom.: 26182 Cov.: 33

Gnomad AFR AF: 0.488

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.667

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.565

GnomAD4 exome AF: 0.633 AC: 33536 AN: 52966 Hom.: 11061 Cov.: 0 AF XY: 0.632 AC XY: 17332 AN XY: 27408

Gnomad4 AFR exome AF: 0.542

Gnomad4 AMR exome AF: 0.381

Gnomad4 ASJ exome AF: 0.599

Gnomad4 EAS exome AF: 0.334

Gnomad4 SAS exome AF: 0.641

Gnomad4 FIN exome AF: 0.692

Gnomad4 NFE exome AF: 0.680

Gnomad4 OTH exome AF: 0.643

GnomAD4 genome AF: 0.577 AC: 87683 AN: 152074 Hom.: 26190 Cov.: 33 AF XY: 0.574 AC XY: 42696 AN XY: 74354

Gnomad4 AFR AF: 0.488

Gnomad4 AMR AF: 0.452

Gnomad4 ASJ AF: 0.589

Gnomad4 EAS AF: 0.339

Gnomad4 SAS AF: 0.620

Gnomad4 FIN AF: 0.667

Gnomad4 NFE AF: 0.658

Gnomad4 OTH AF: 0.563

Alfa AF: 0.632 Hom.: 48471

Bravo AF: 0.551

Asia WGS AF: 0.472 AC: 1642 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.34
DANN	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs3776455; hg19: chr5-7896511;