rs326119

chr5-7869970-C-Achr5-7869970-C-Gchr5-7869970-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002454.3(MTRR):c.-26+755C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 967,338 control chromosomes in the GnomAD database, including 130,365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.57 (25058 hom., cov: 33)
  • Exomes 𝑓: 0.51 (105307 hom.)
• Consequence: MTRR NM_002454.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.320

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 5-7869970-C-A is Benign according to our data. Variant chr5-7869970-C-A is described in ClinVar as [Benign]. Clinvar id is 1166106.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRR	NM_002454.3	c.-26+755C>A		intron_variant		ENST00000440940.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRR	ENST00000440940.7	c.-26+755C>A		intron_variant		1	NM_002454.3	P1

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86184 AN: 151910 Hom.: 25034 Cov.: 33

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.637

Gnomad ASJ AF: 0.421

Gnomad EAS AF: 0.656

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.496

Gnomad OTH AF: 0.552

GnomAD4 exome AF: 0.506 AC: 412728 AN: 815310 Hom.: 105307 AF XY: 0.506 AC XY: 190903 AN XY: 377150

Gnomad4 AFR exome AF: 0.679

Gnomad4 AMR exome AF: 0.684

Gnomad4 ASJ exome AF: 0.425

Gnomad4 EAS exome AF: 0.653

Gnomad4 SAS exome AF: 0.624

Gnomad4 FIN exome AF: 0.507

Gnomad4 NFE exome AF: 0.499

Gnomad4 OTH exome AF: 0.526

GnomAD4 genome AF: 0.567 AC: 86257 AN: 152028 Hom.: 25058 Cov.: 33 AF XY: 0.572 AC XY: 42460 AN XY: 74292

Gnomad4 AFR AF: 0.663

Gnomad4 AMR AF: 0.637

Gnomad4 ASJ AF: 0.421

Gnomad4 EAS AF: 0.657

Gnomad4 SAS AF: 0.639

Gnomad4 FIN AF: 0.533

Gnomad4 NFE AF: 0.496

Gnomad4 OTH AF: 0.550

Alfa AF: 0.421 Hom.: 1812

Bravo AF: 0.575

Asia WGS AF: 0.629 AC: 2189 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylcobalamin deficiency type cblE Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	1.2
Dann	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs326119; hg19: chr5-7870083;