chr15-79845218-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_006441.4(MTHFS):c.604A>G(p.Thr202Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0852 in 1,614,148 control chromosomes in the GnomAD database, including 6,373 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T202I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.075 ( 478 hom., cov: 32)

Exomes 𝑓: 0.086 ( 5895 hom. )

Consequence

MTHFS
NM_006441.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.55

Publications

29 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017362237).

BP6

Variant 15-79845218-T-C is Benign according to our data. Variant chr15-79845218-T-C is described in ClinVar as Benign. ClinVar VariationId is 2038284.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0881 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFS	NM_006441.4 link	c.604A>G	p.Thr202Ala	missense_variant	Exon 3 of 3	ENST00000258874.4	NP_006432.1	P49914-1
ST20-MTHFS	NM_001199760.2 link	c.532A>G	p.Thr178Ala	missense_variant	Exon 4 of 4		NP_001186689.1	A0A0A6YYL1
MTHFS	NM_001199758.1 link	c.433A>G	p.Thr145Ala	missense_variant	Exon 3 of 3		NP_001186687.1	P49914
MTHFS	NR_037654.2 link	n.711A>G		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.604A>G	p.Thr202Ala	missense_variant	Exon 3 of 3	1	NM_006441.4	ENSP00000258874.4		P49914-1
ST20-MTHFS	ENST00000479961.1 link	c.532A>G	p.Thr178Ala	missense_variant	Exon 4 of 4	3		ENSP00000455643.1		A0A0A6YYL1

Frequencies

GnomAD3 genomes

AF:

0.0746

AC:

11351

AN:

152178

Hom.:

478

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0710

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0586

Gnomad ASJ

AF:

0.0832

Gnomad EAS

AF:

0.00905

Gnomad SAS

AF:

0.0352

Gnomad FIN

AF:

0.0633

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0900

Gnomad OTH

AF:

0.0732

GnomAD2 exomes

AF:

0.0666

AC:

16739

AN:

251310

AF XY:

0.0674

show subpopulations

Gnomad AFR exome

AF:

0.0706

Gnomad AMR exome

AF:

0.0370

Gnomad ASJ exome

AF:

0.0804

Gnomad EAS exome

AF:

0.00761

Gnomad FIN exome

AF:

0.0656

Gnomad NFE exome

AF:

0.0917

Gnomad OTH exome

AF:

0.0712

GnomAD4 exome

AF:

0.0863

AC:

126177

AN:

1461852

Hom.:

5895

Cov.:

AF XY:

0.0848

AC XY:

61642

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0717

AC:

2399

AN:

33480

American (AMR)

AF:

0.0411

AC:

1836

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0781

AC:

2042

AN:

26136

East Asian (EAS)

AF:

0.00877

AC:

348

AN:

39700

South Asian (SAS)

AF:

0.0374

AC:

3230

AN:

86256

European-Finnish (FIN)

AF:

0.0691

AC:

3689

AN:

53418

Middle Eastern (MID)

AF:

0.0692

AC:

399

AN:

5768

European-Non Finnish (NFE)

AF:

0.0966

AC:

107417

AN:

1111976

Other (OTH)

AF:

0.0798

AC:

4817

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

6673

13345

20018

26690

33363

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3922

7844

11766

15688

19610

<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

AF:

0.0746

AC:

11358

AN:

152296

Hom.:

478

Cov.:

AF XY:

0.0712

AC XY:

5305

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0711

AC:

2953

AN:

41558

American (AMR)

AF:

0.0585

AC:

895

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0832

AC:

289

AN:

3472

East Asian (EAS)

AF:

0.00907

AC:

AN:

5184

South Asian (SAS)

AF:

0.0356

AC:

172

AN:

4830

European-Finnish (FIN)

AF:

0.0633

AC:

672

AN:

10614

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0900

AC:

6122

AN:

68012

Other (OTH)

AF:

0.0724

AC:

153

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

527

1055

1582

2110

2637

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0847

Hom.:

2787

Bravo

AF:

0.0763

TwinsUK

AF:

0.0992

AC:

368

ALSPAC

AF:

0.0996

AC:

384

ESP6500AA

AF:

0.0692

AC:

305

ESP6500EA

AF:

0.0887

AC:

763

ExAC

AF:

0.0678

AC:

8227

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0894

EpiControl

AF:

0.0884

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.0020

(source)

DANN

Benign

0.27

DEOGEN2

Benign

0.28

T;.;.;.

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0034

LIST_S2

Benign

0.19

T;T;.;T

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.;.;.

PhyloP100

-1.6

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.31

N;.;.;N

REVEL

Benign

0.052

Sift

Benign

0.76

T;.;.;T

Sift4G

Benign

0.48

T;T;T;T

Polyphen

0.0

B;.;.;.

Vest4

0.028

MPC

0.24

ClinPred

0.0029

GERP RS

-9.9

Varity_R

0.013

gMVP

0.27

Mutation Taster

=99/1

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over