rs145006491

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000254.3(MTR):c.1033G>A(p.Val345Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000848 in 1,614,010 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 9 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 5 hom. )

Consequence

MTR
NM_000254.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.49

Variant links:

Genes affected

MTR (HGNC:7468): (5-methyltetrahydrofolate-homocysteine methyltransferase) This gene encodes the 5-methyltetrahydrofolate-homocysteine methyltransferase. This enzyme, also known as cobalamin-dependent methionine synthase, catalyzes the final step in methionine biosynthesis. Mutations in MTR have been identified as the underlying cause of methylcobalamin deficiency complementation group G. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

MTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant where missense usually causes diseases, MTR

BP4

Computational evidence support a benign effect (MetaRNN=0.0057397485).

BP6

Variant 1-236829226-G-A is Benign according to our data. Variant chr1-236829226-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 296557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236829226-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0048 (731/152230) while in subpopulation AFR AF= 0.0168 (697/41522). AF 95% confidence interval is 0.0158. There are 9 homozygotes in gnomad4. There are 352 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTR	NM_000254.3 linkuse as main transcript	c.1033G>A	p.Val345Ile	missense_variant	12/33	ENST00000366577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTR	ENST00000366577.10 linkuse as main transcript	c.1033G>A	p.Val345Ile	missense_variant	12/33	1	NM_000254.3	P1	Q99707-1

Frequencies

GnomAD3 genomes

AF:

0.00480

AC:

730

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0168

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00107

AC:

268

AN:

251452

Hom.:

AF XY:

0.000721

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0151

Gnomad AMR exome

AF:

0.000520

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:

0.0000264

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000436

AC:

637

AN:

1461780

Hom.:

Cov.:

AF XY:

0.000381

AC XY:

277

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0159

Gnomad4 AMR exome

AF:

0.000715

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.000878

GnomAD4 genome

AF:

0.00480

AC:

731

AN:

152230

Hom.:

Cov.:

AF XY:

0.00473

AC XY:

352

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0168

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.000594

Hom.:

Bravo

AF:

0.00501

ESP6500AA

AF:

0.0163

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00129

AC:

157

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2020	- -

Methylcobalamin deficiency type cblG

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

Cadd

Benign

Dann

Uncertain

0.98

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

L;L

MutationTaster

Benign

0.91

D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.64

N;N

REVEL

Benign

0.033

Sift

Benign

0.29

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.0

.;B

Vest4

0.22

MVP

0.27

MPC

0.33

ClinPred

0.031

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.049

gMVP

0.47

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

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