Variant rs12030699 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_000254.3(MTR):c.3496C>A(p.Leu1166Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000687 in 1,600,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1166L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

MTR
NM_000254.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.07

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:

MTR (HGNC:):

MTR links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MTR. . Gene score misZ 2.0433 (greater than the threshold 3.09). Trascript score misZ 3.2999 (greater than threshold 3.09). GenCC has associacion of gene with methylcobalamin deficiency type cblG.

BP4

Computational evidence support a benign effect (MetaRNN=0.18912488).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTR	NM_000254.3 linkuse as main transcript	c.3496C>A	p.Leu1166Met	missense_variant	31/33	ENST00000366577.10	NP_000245.2	Q99707-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10 linkuse as main transcript	c.3496C>A	p.Leu1166Met	missense_variant	31/33	1	NM_000254.3	ENSP00000355536.5		Q99707-1
MTR	ENST00000366576.3 linkuse as main transcript	c.2158C>A	p.Leu720Met	missense_variant	18/20	1		ENSP00000355535.3		B1ANE3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000132

AC:

AN:

227274

Hom.:

AF XY:

0.0000163

AC XY:

AN XY:

122672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000108

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000690

AC:

AN:

1448822

Hom.:

Cov.:

AF XY:

0.00000973

AC XY:

AN XY:

719214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000163

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

.;T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Uncertain

0.094

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.3

.;L;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.57

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.063

T;T;T

Sift4G

Uncertain

0.025

D;D;D

Polyphen

0.022

.;B;.

Vest4

0.36

MutPred

0.63

.;Gain of MoRF binding (P = 0.0699);.;

MVP

0.63

MPC

0.49

ClinPred

0.18

GERP RS

2.3

Varity_R

0.21

gMVP

0.53

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over