14-64449447-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005956.4(MTHFD1):c.2282C>T(p.Thr761Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00633 in 1,613,056 control chromosomes in the GnomAD database, including 362 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T761T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.026 ( 152 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 210 hom. )

Consequence

MTHFD1
NM_005956.4 missense, splice_region

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 6.09

Publications

15 publications found

Variant links:

Genes affected

MTHFD1 (HGNC:7432): (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1) This gene encodes a protein that possesses three distinct enzymatic activities, 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase. Each of these activities catalyzes one of three sequential reactions in the interconversion of 1-carbon derivatives of tetrahydrofolate, which are substrates for methionine, thymidylate, and de novo purine syntheses. The trifunctional enzymatic activities are conferred by two major domains, an aminoterminal portion containing the dehydrogenase and cyclohydrolase activities and a larger synthetase domain. [provided by RefSeq, Jul 2008]

MTHFD1 links:

ZBTB25 (HGNC:13112): (zinc finger and BTB domain containing 25) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZBTB25 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008836538).

BP6

Variant 14-64449447-C-T is Benign according to our data. Variant chr14-64449447-C-T is described in ClinVar as Benign. ClinVar VariationId is 1166610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFD1	NM_005956.4 link	c.2282C>T	p.Thr761Met	missense_variant, splice_region_variant	Exon 24 of 28	ENST00000652337.1	NP_005947.3	P11586
MTHFD1	NM_001364837.1 link	c.2282C>T	p.Thr761Met	missense_variant, splice_region_variant	Exon 24 of 27		NP_001351766.1
ZBTB25	NM_001304508.1 link	c.*104G>A		3_prime_UTR_variant	Exon 3 of 3		NP_001291437.1	G3V2K3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1 link	c.2282C>T	p.Thr761Met	missense_variant, splice_region_variant	Exon 24 of 28		NM_005956.4	ENSP00000498336.1		P11586

Frequencies

GnomAD3 genomes

AF:

0.0261

AC:

3973

AN:

152152

Hom.:

151

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0277

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.0162

GnomAD2 exomes

AF:

0.00987

AC:

2478

AN:

251140

AF XY:

0.00882

show subpopulations

Gnomad AFR exome

AF:

0.0911

Gnomad AMR exome

AF:

0.00575

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000361

Gnomad OTH exome

AF:

0.00539

GnomAD4 exome

AF:

0.00427

AC:

6233

AN:

1460786

Hom.:

210

Cov.:

AF XY:

0.00451

AC XY:

3280

AN XY:

726696

show subpopulations

African (AFR)

AF:

0.0947

AC:

3168

AN:

33446

American (AMR)

AF:

0.00599

AC:

268

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0230

AC:

1984

AN:

86206

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00630

AC:

AN:

4918

European-Non Finnish (NFE)

AF:

0.000300

AC:

334

AN:

1111960

Other (OTH)

AF:

0.00735

AC:

443

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

349

698

1048

1397

1746

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<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:

0.0262

AC:

3984

AN:

152270

Hom.:

152

Cov.:

AF XY:

0.0255

AC XY:

1901

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0868

AC:

3605

AN:

41530

American (AMR)

AF:

0.0122

AC:

187

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.0275

AC:

133

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68024

Other (OTH)

AF:

0.0161

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

198

395

593

790

988

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.00903

Hom.:

195

Bravo

AF:

0.0296

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0892

AC:

393

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0118

AC:

1438

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

.;D

MetaRNN

Benign

0.0088

T;T

MetaSVM

Benign

-0.78

PhyloP100

6.1

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-4.7

D;.

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;.

Vest4

0.20

MPC

0.54

ClinPred

0.086

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=41/59

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