14-64400804-C-T

Position:

chr14-64400804-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005956.4(MTHFD1):c.53C>T(p.Ala18Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00385 in 1,612,920 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 16 hom. )

Consequence

MTHFD1
NM_005956.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.40

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008382082).

BP6

Variant 14-64400804-C-T is Benign according to our data. Variant chr14-64400804-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 791428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64400804-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00324 (493/152266) while in subpopulation NFE AF= 0.00479 (326/68010). AF 95% confidence interval is 0.00437. There are 3 homozygotes in gnomad4. There are 223 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFD1	NM_005956.4 linkuse as main transcript	c.53C>T	p.Ala18Val	missense_variant	2/28	ENST00000652337.1	NP_005947.3
MTHFD1	NM_001364837.1 linkuse as main transcript	c.53C>T	p.Ala18Val	missense_variant	2/27		NP_001351766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1 linkuse as main transcript	c.53C>T	p.Ala18Val	missense_variant	2/28		NM_005956.4	ENSP00000498336	P1

Frequencies

GnomAD3 genomes

AF:

0.00323

AC:

492

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00478

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00346

AC:

868

AN:

250952

Hom.:

AF XY:

0.00351

AC XY:

476

AN XY:

135626

show subpopulations

Gnomad AFR exome

AF:

0.000678

Gnomad AMR exome

AF:

0.00295

Gnomad ASJ exome

AF:

0.0168

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00246

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00411

Gnomad OTH exome

AF:

0.00506

GnomAD4 exome

AF:

0.00391

AC:

5718

AN:

1460654

Hom.:

Cov.:

AF XY:

0.00404

AC XY:

2935

AN XY:

726678

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.00275

Gnomad4 ASJ exome

AF:

0.0161

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00246

Gnomad4 FIN exome

AF:

0.000581

Gnomad4 NFE exome

AF:

0.00411

Gnomad4 OTH exome

AF:

0.00466

GnomAD4 genome

AF:

0.00324

AC:

493

AN:

152266

Hom.:

Cov.:

AF XY:

0.00300

AC XY:

223

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.0179

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00479

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00338

Hom.:

Bravo

AF:

0.00330

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00337

AC:

409

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00692

EpiControl

AF:

0.00641

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

MTHFD1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.93

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.47

LIST_S2

Uncertain

0.92

.;.;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.0084

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.2

N;.;.

REVEL

Benign

0.038

Sift

Benign

0.047

D;.;.

Sift4G

Benign

0.079

T;T;T

Polyphen

0.034

B;.;.

Vest4

0.23

MVP

0.32

MPC

0.36

ClinPred

0.0040

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over