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

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_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.

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

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 made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a mutagenesis_site Reduces activity by 98%. (size 0) in uniprot entity MTHFS_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFS	NM_006441.4 link	c.434G>T	p.Arg145Leu	missense_variant	Exon 3 of 3	ENST00000258874.4	NP_006432.1	P49914-1
ST20-MTHFS	NM_001199760.2 link	c.362G>T	p.Arg121Leu	missense_variant	Exon 4 of 4		NP_001186689.1	A0A0A6YYL1
MTHFS	NM_001199758.1 link	c.263G>T	p.Arg88Leu	missense_variant	Exon 3 of 3		NP_001186687.1	P49914
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		P49914-1
ST20-MTHFS	ENST00000479961.1 link	c.362G>T	p.Arg121Leu	missense_variant	Exon 4 of 4	3		ENSP00000455643.1		A0A0A6YYL1

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

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:

0.00

Gnomad4 NFE exome

AF:

0.00000180

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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

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;.;.;.;.

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

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over