Genetic Variant NM_000254.3:c.2758C>T (chr1-236885202-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The NM_000254.3(MTR):c.2758C>T(p.His920Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,088 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. H920D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

MTR
NM_000254.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.22

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-236885202-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 14280.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3 link	c.2758C>T	p.His920Tyr	missense_variant	Exon 26 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.2758C>T	p.His920Tyr	missense_variant	Exon 26 of 33	1	NM_000254.3	ENSP00000355536.5		Q99707-1
MTR	ENST00000366576.3 link	c.1420C>T	p.His474Tyr	missense_variant	Exon 13 of 20	1		ENSP00000355535.3		B1ANE3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251226

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135810

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:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.97e-7

AC:

AN:

1435088

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715838

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:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.58

.;D;.

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.55

D;D;D

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.2

.;M;.

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Uncertain

0.45

Sift

Benign

0.19

T;T;T

Sift4G

Benign

0.31

T;T;T

Polyphen

0.033

.;B;.

Vest4

0.64

MutPred

0.42

.;Gain of phosphorylation at H920 (P = 0.0613);.;

MVP

0.73

MPC

0.52

ClinPred

0.53

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.81

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