dbSNP rs753635972: MTHFS:p.Arg145Leu (chr15-79845388-C-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

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

The NM_006441.4(MTHFS):c.434G>T(p.Arg145Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,870 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. R145Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MTHFS
NM_006441.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.19

Publications

0 publications found

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:44655): (ST20-MTHFS readthrough) This locus represents naturally occurring read-through transcription between the neighboring suppressor of tumorigenicity 20 and 5,10-methenyltetrahydrofolate synthetase (5-formyltetrahydrofolate cyclo-ligase) genes on chromosome 15. The read-through transcript produces a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Dec 2010]

ST20-MTHFS links:

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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 chr15-79845388-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522831.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MTHFS	NM_006441.4 link	c.434G>T	p.Arg145Leu	missense_variant	Exon 3 of 3	ENST00000258874.4	NP_006432.1
ST20-MTHFS	NM_001199760.2 link	c.362G>T	p.Arg121Leu	missense_variant	Exon 4 of 4		NP_001186689.1
MTHFS	NM_001199758.1 link	c.263G>T	p.Arg88Leu	missense_variant	Exon 3 of 3		NP_001186687.1
MTHFS	NR_037654.2 link	n.541G>T		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFS	ENST00000258874.4 link	c.434G>T	p.Arg145Leu	missense_variant	Exon 3 of 3	1	NM_006441.4	ENSP00000258874.4
ST20-MTHFS	ENST00000479961.1 link	c.362G>T	p.Arg121Leu	missense_variant	Exon 4 of 4	3		ENSP00000455643.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.;.;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;.;D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

4.0

H;.;.;.;.

PhyloP100

7.2

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-6.5

D;.;.;D;.

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;.;.;D;.

Sift4G

Uncertain

0.0020

D;D;D;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.91

MutPred

0.89

Loss of methylation at R145 (P = 0.0175);.;.;.;.;

MVP

0.99

MPC

0.98

ClinPred

1.0

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.93

Mutation Taster

=1/99

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

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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