14-64449470-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_001364837.1(MTHFD1):c.2305C>T(p.Leu769Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0055 in 1,613,774 control chromosomes in the GnomAD database, including 402 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L769L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.029 ( 192 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 210 hom. )

Consequence

MTHFD1
NM_001364837.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.04

Publications

10 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=0.002995789).

BP6

Variant 14-64449470-C-T is Benign according to our data. Variant chr14-64449470-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 779686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.097 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364837.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTHFD1	NM_005956.4	MANE Select	c.2305C>T	p.Leu769Phe	missense	Exon 24 of 28	NP_005947.3
MTHFD1	NM_001364837.1		c.2305C>T	p.Leu769Phe	missense	Exon 24 of 27	NP_001351766.1
ZBTB25	NM_001304508.1		c.*81G>A		3_prime_UTR	Exon 3 of 3	NP_001291437.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MTHFD1	ENST00000652337.1	MANE Select	c.2305C>T	p.Leu769Phe	missense	Exon 24 of 28	ENSP00000498336.1
ZBTB25	ENST00000555220.5	TSL:1	c.*81G>A		3_prime_UTR	Exon 3 of 3	ENSP00000450718.1
MTHFD1	ENST00000545908.6	TSL:2	c.2305C>T	p.Leu769Phe	missense	Exon 24 of 27	ENSP00000438588.2

Frequencies

GnomAD3 genomes

AF:

0.0285

AC:

4337

AN:

152168

Hom.:

192

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0997

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00884

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.0192

GnomAD2 exomes

AF:

0.00761

AC:

1911

AN:

251250

AF XY:

0.00535

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.00520

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000317

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00310

AC:

4533

AN:

1461488

Hom.:

210

Cov.:

AF XY:

0.00266

AC XY:

1933

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.106

AC:

3551

AN:

33470

American (AMR)

AF:

0.00572

AC:

256

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000244

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00606

AC:

AN:

5442

European-Non Finnish (NFE)

AF:

0.000190

AC:

211

AN:

1112012

Other (OTH)

AF:

0.00760

AC:

459

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

250

500

749

999

1249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.0285

AC:

4342

AN:

152286

Hom.:

192

Cov.:

AF XY:

0.0274

AC XY:

2040

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0996

AC:

4138

AN:

41562

American (AMR)

AF:

0.00876

AC:

134

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68020

Other (OTH)

AF:

0.0190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

200

400

599

799

999

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0108

Hom.:

150

Bravo

AF:

0.0326

ESP6500AA

AF:

0.0990

AC:

436

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00925

AC:

1123

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000474

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.056

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0030

MetaSVM

Benign

-1.1

PhyloP100

3.0

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.079

Sift

Uncertain

0.0090

Sift4G

Benign

0.099

Polyphen

0.077

Vest4

0.64

MVP

0.34

MPC

1.1

ClinPred

0.043

GERP RS

4.3

Mutation Taster

=93/7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over