chr5-7889103-G-A

Position:

chr5-7889103-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002454.3(MTRR):c.1155G>A(p.Leu385Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,613,972 control chromosomes in the GnomAD database, including 2,193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.044 ( 274 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1919 hom. )

Consequence

MTRR
NM_002454.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.54

Variant links:

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 links:

MTRR (HGNC:):

MTRR links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 5-7889103-G-A is Benign according to our data. Variant chr5-7889103-G-A is described in ClinVar as [Benign]. Clinvar id is 138292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-7889103-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=3.54 with no splicing effect.

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/exons	MANE	Protein	UniProt
MTRR	NM_002454.3 linkuse as main transcript	c.1155G>A	p.Leu385Leu	synonymous_variant	9/15	ENST00000440940.7	NP_002445.2	Q9UBK8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTRR	ENST00000440940.7 linkuse as main transcript	c.1155G>A	p.Leu385Leu	synonymous_variant	9/15	1	NM_002454.3	ENSP00000402510.2		Q9UBK8-2

Frequencies

GnomAD3 genomes

AF:

0.0440

AC:

6696

AN:

152062

Hom.:

273

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0243

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.0875

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.185

Gnomad SAS

AF:

0.0383

Gnomad FIN

AF:

0.0713

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0334

Gnomad OTH

AF:

0.0431

GnomAD3 exomes

AF:

0.0612

AC:

15393

AN:

251406

Hom.:

811

AF XY:

0.0556

AC XY:

7561

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.0255

Gnomad AMR exome

AF:

0.140

Gnomad ASJ exome

AF:

0.0136

Gnomad EAS exome

AF:

0.184

Gnomad SAS exome

AF:

0.0344

Gnomad FIN exome

AF:

0.0697

Gnomad NFE exome

AF:

0.0332

Gnomad OTH exome

AF:

0.0473

GnomAD4 exome

AF:

0.0392

AC:

57359

AN:

1461792

Hom.:

1919

Cov.:

AF XY:

0.0386

AC XY:

28063

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.0232

Gnomad4 AMR exome

AF:

0.135

Gnomad4 ASJ exome

AF:

0.0135

Gnomad4 EAS exome

AF:

0.174

Gnomad4 SAS exome

AF:

0.0344

Gnomad4 FIN exome

AF:

0.0678

Gnomad4 NFE exome

AF:

0.0308

Gnomad4 OTH exome

AF:

0.0402

GnomAD4 genome

AF:

0.0440

AC:

6698

AN:

152180

Hom.:

274

Cov.:

AF XY:

0.0469

AC XY:

3491

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0244

Gnomad4 AMR

AF:

0.0874

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.185

Gnomad4 SAS

AF:

0.0381

Gnomad4 FIN

AF:

0.0713

Gnomad4 NFE

AF:

0.0334

Gnomad4 OTH

AF:

0.0417

Alfa

AF:

0.0403

Hom.:

150

Bravo

AF:

0.0447

Asia WGS

AF:

0.117

AC:

406

AN:

3478

EpiCase

AF:

0.0266

EpiControl

AF:

0.0279

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 23, 2014

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. -

Disorders of Intracellular Cobalamin Metabolism

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Methylcobalamin deficiency type cblE

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Methylcobalamin deficiency type cblE;C1866558:Neural tube defects, folate-sensitive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

7.9

DANN

Benign

0.97

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over