rs121913578

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000254.3(MTR):c.3518C>A(p.Pro1173Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1173L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MTR
NM_000254.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.51

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-236895470-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 14278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.944

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000254.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTR	NM_000254.3	MANE Select	c.3518C>A	p.Pro1173Gln	missense	Exon 31 of 33	NP_000245.2
MTR	NM_001291939.1		c.3365C>A	p.Pro1122Gln	missense	Exon 30 of 32	NP_001278868.1
MTR	NM_001410942.1		c.3329C>A	p.Pro1110Gln	missense	Exon 29 of 31	NP_001397871.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTR	ENST00000366577.10	TSL:1 MANE Select	c.3518C>A	p.Pro1173Gln	missense	Exon 31 of 33	ENSP00000355536.5
MTR	ENST00000535889.6	TSL:1	c.3365C>A	p.Pro1122Gln	missense	Exon 30 of 32	ENSP00000441845.1
MTR	ENST00000366576.3	TSL:1	c.2180C>A	p.Pro727Gln	missense	Exon 18 of 20	ENSP00000355535.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1444834

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716934

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33184

American (AMR)

AF:

0.00

AC:

AN:

43084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25654

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38946

South Asian (SAS)

AF:

0.00

AC:

AN:

83240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51992

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103344

Other (OTH)

AF:

0.00

AC:

AN:

59638

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

0.80

MutationAssessor

Pathogenic

4.5

PhyloP100

7.5

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.7

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.81

MutPred

0.75

Loss of catalytic residue at P1173 (P = 0.0299)

MVP

0.95

MPC

1.2

ClinPred

1.0

GERP RS

5.6

Varity_R

0.99

gMVP

0.94

Mutation Taster

=4/96

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over