rs115289458

chr5-7883202-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS1

The NM_002454.3(MTRR):c.828G>A(p.Val276=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 1,614,192 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (3 hom.)
• Consequence: MTRR NM_002454.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.296

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=-0.41).
• BP6: Variant 5-7883202-G-A is Benign according to our data. Variant chr5-7883202-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 384902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00111 (169/152330) while in subpopulation AFR AF= 0.00378 (157/41572). AF 95% confidence interval is 0.00329. There are 0 homozygotes in gnomad4. There are 77 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRR	NM_002454.3	c.828G>A	p.Val276=	synonymous_variant	6/15	ENST00000440940.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRR	ENST00000440940.7	c.828G>A	p.Val276=	synonymous_variant	6/15	1	NM_002454.3	P1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00374

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000390 AC: 98 AN: 251444 Hom.: 0 AF XY: 0.000324 AC XY: 44 AN XY: 135898

Gnomad AFR exome AF: 0.00431

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000180 AC: 263 AN: 1461862 Hom.: 3 Cov.: 32 AF XY: 0.000187 AC XY: 136 AN XY: 727232

Gnomad4 AFR exome AF: 0.00478

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74498

Gnomad4 AFR AF: 0.00378

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000667 Hom.: 1

Bravo AF: 0.00145

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 30, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Methylcobalamin deficiency type cblE Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	3.1
Dann	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs115289458; hg19: chr5-7883315;