Genetic Variant NM_000254.3:c.3496C>G (chr1-236895448-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000254.3(MTR):c.3496C>G(p.Leu1166Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,448,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

MTR
NM_000254.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.07

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

methylcobalamin deficiency type cblG
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P

MTR links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15394506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3 link	c.3496C>G	p.Leu1166Val	missense_variant	Exon 31 of 33	ENST00000366577.10	NP_000245.2	Q99707-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10 link	c.3496C>G	p.Leu1166Val	missense_variant	Exon 31 of 33	1	NM_000254.3	ENSP00000355536.5		Q99707-1
MTR	ENST00000366576.3 link	c.2158C>G	p.Leu720Val	missense_variant	Exon 18 of 20	1		ENSP00000355535.3		B1ANE3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1448824

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719216

show subpopulations

African (AFR)

AF:

0.0000901

AC:

AN:

33302

American (AMR)

AF:

0.0000230

AC:

AN:

43412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25686

East Asian (EAS)

AF:

0.00

AC:

AN:

39218

South Asian (SAS)

AF:

0.00

AC:

AN:

83836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105530

Other (OTH)

AF:

0.00

AC:

AN:

59780

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

.;T;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.044

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

-0.63

.;N;.

PhyloP100

2.1

PrimateAI

Benign

0.43

PROVEAN

Benign

0.85

N;N;N

REVEL

Benign

0.18

Sift

Benign

0.19

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.11

MutPred

0.62

.;Gain of MoRF binding (P = 0.0851);.;

MVP

0.63

MPC

0.41

ClinPred

0.21

GERP RS

2.3

Varity_R

0.11

gMVP

0.52

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over