rs368619885

Positions:

chr1-236835668-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_000254.3(MTR):c.1310C>A(p.Ser437Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,611,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S437S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

MTR
NM_000254.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.37

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTR	NM_000254.3 linkuse as main transcript	c.1310C>A	p.Ser437Tyr	missense_variant	14/33	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.1310C>A	p.Ser437Tyr	missense_variant	14/33	1	NM_000254.3	ENSP00000355536.5		Q99707-1
MTR	ENST00000366576.3 linkuse as main transcript	c.53C>A	p.Ser18Tyr	missense_variant	1/20	1		ENSP00000355535.3		B1ANE3

Frequencies

GnomAD3 genomes

AF:

0.0000533

AC:

AN:

150098

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251482

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000533

AC:

AN:

150098

Hom.:

Cov.:

AF XY:

0.0000684

AC XY:

AN XY:

73090

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000430

Hom.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylcobalamin deficiency type cblG

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 05, 2022

This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 437 of the MTR protein (p.Ser437Tyr). This variant is present in population databases (rs368619885, gnomAD 0.005%). This missense change has been observed in individual(s) with methylcobalamin deficiency G disorder (PMID: 12068375). ClinVar contains an entry for this variant (Variation ID: 296563). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Disorders of Intracellular Cobalamin Metabolism

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The MTR c.1310C>A (p.Ser437Tyr) missense variant has been reported in one study in which it was identified in a compound heterozygous state with a second missense variant in one individual with methylcobalamin deficiency G disorder (Watkins et al. 2002). The p.Ser437Tyr variant was absent from 50 controls and is reported at a frequency of 0.00012 in the European-American population of the Exome Sequencing Project, but this is based on one allele only so is presumed to be rare. Based on the limited evidence, the p.Ser437Tyr variant is classified as a variant of unknown significance but suspicious for pathogenicity for disorders of intracellular cobalamin metabolism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 02, 2021

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12068375) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.9

H;H;.

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.0

D;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.86

MVP

0.96

MPC

1.4

ClinPred

0.99

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.72

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