15-79889152-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006441.4(MTHFS):c.320C>T(p.Thr107Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,614,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 0 hom. )

Consequence

MTHFS
NM_006441.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.05

Variant links:

Genes affected

MTHFS (HGNC:7437): (methenyltetrahydrofolate synthetase) The protein encoded by this gene is an enzyme that catalyzes the conversion of 5-formyltetrahydrofolate to 5,10-methenyltetrahydrofolate, a precursor of reduced folates involved in 1-carbon metabolism. An increased activity of the encoded protein can result in an increased folate turnover rate and folate depletion. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2011]

MTHFS links:

ST20-MTHFS (HGNC:):

ST20-MTHFS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11966547).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MTHFS	NM_006441.4 linkuse as main transcript	c.320C>T	p.Thr107Ile	missense_variant	2/3	ENST00000258874.4
ST20-MTHFS	NM_001199760.2 linkuse as main transcript	c.248C>T	p.Thr83Ile	missense_variant	3/4
MTHFS	NM_001199758.1 linkuse as main transcript	c.149C>T	p.Thr50Ile	missense_variant	2/3
MTHFS	NR_037654.2 linkuse as main transcript	n.427C>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFS	ENST00000258874.4 linkuse as main transcript	c.320C>T	p.Thr107Ile	missense_variant	2/3	1	NM_006441.4	P1	P49914-1
MTHFS	ENST00000559722.2 linkuse as main transcript	c.407C>T	p.Thr136Ile	missense_variant	2/3	2
MTHFS	ENST00000560919.5 linkuse as main transcript	c.*266C>T		3_prime_UTR_variant, NMD_transcript_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.000710

AC:

108

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000768

AC:

193

AN:

251454

Hom.:

AF XY:

0.000824

AC XY:

112

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00118

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00114

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00126

AC:

1837

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

917

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.00118

Gnomad4 FIN exome

AF:

0.000449

Gnomad4 NFE exome

AF:

0.00146

Gnomad4 OTH exome

AF:

0.00114

GnomAD4 genome

AF:

0.000709

AC:

108

AN:

152298

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00109

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000954

Hom.:

Bravo

AF:

0.000688

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000889

AC:

108

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.00136

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 107 of the MTHFS protein (p.Thr107Ile). This variant is present in population databases (rs140052193, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with MTHFS-related conditions. ClinVar contains an entry for this variant (Variation ID: 2054000). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.;.;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;.;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.12

T;T;T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Pathogenic

3.4

M;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.4

D;.;.;D;.

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

D;.;.;D;.

Sift4G

Uncertain

0.0040

D;D;D;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.83

MVP

0.66

MPC

0.91

ClinPred

0.25

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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