Variant rs2236224 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005956.4(MTHFD1):c.2136+31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 1,609,322 control chromosomes in the GnomAD database, including 128,880 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 9569 hom., cov: 32)

Exomes 𝑓: 0.40 ( 119311 hom. )

Consequence

MTHFD1
NM_005956.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.840

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:

MTHFD1 (HGNC:):

MTHFD1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 14-64442433-G-A is Benign according to our data. Variant chr14-64442433-G-A is described in ClinVar as [Benign]. Clinvar id is 1321176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFD1	NM_005956.4 linkuse as main transcript	c.2136+31G>A		intron_variant		ENST00000652337.1	NP_005947.3	P11586
MTHFD1	NM_001364837.1 linkuse as main transcript	c.2136+31G>A		intron_variant			NP_001351766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1 linkuse as main transcript	c.2136+31G>A		intron_variant			NM_005956.4	ENSP00000498336.1		P11586

Frequencies

GnomAD3 genomes

AF:

0.330

AC:

50187

AN:

151964

Hom.:

9563

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.481

Gnomad AMR

AF:

0.478

Gnomad ASJ

AF:

0.377

Gnomad EAS

AF:

0.298

Gnomad SAS

AF:

0.431

Gnomad FIN

AF:

0.374

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.399

Gnomad OTH

AF:

0.340

GnomAD3 exomes

AF:

0.396

AC:

98712

AN:

249464

Hom.:

20646

AF XY:

0.397

AC XY:

53649

AN XY:

135032

show subpopulations

Gnomad AFR exome

AF:

0.133

Gnomad AMR exome

AF:

0.551

Gnomad ASJ exome

AF:

0.384

Gnomad EAS exome

AF:

0.296

Gnomad SAS exome

AF:

0.433

Gnomad FIN exome

AF:

0.379

Gnomad NFE exome

AF:

0.397

Gnomad OTH exome

AF:

0.386

GnomAD4 exome

AF:

0.400

AC:

583073

AN:

1457240

Hom.:

119311

Cov.:

AF XY:

0.401

AC XY:

290823

AN XY:

725164

show subpopulations

Gnomad4 AFR exome

AF:

0.123

Gnomad4 AMR exome

AF:

0.542

Gnomad4 ASJ exome

AF:

0.384

Gnomad4 EAS exome

AF:

0.303

Gnomad4 SAS exome

AF:

0.430

Gnomad4 FIN exome

AF:

0.379

Gnomad4 NFE exome

AF:

0.407

Gnomad4 OTH exome

AF:

0.383

GnomAD4 genome

AF:

0.330

AC:

50212

AN:

152082

Hom.:

9569

Cov.:

AF XY:

0.333

AC XY:

24729

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.136

Gnomad4 AMR

AF:

0.479

Gnomad4 ASJ

AF:

0.377

Gnomad4 EAS

AF:

0.298

Gnomad4 SAS

AF:

0.430

Gnomad4 FIN

AF:

0.374

Gnomad4 NFE

AF:

0.399

Gnomad4 OTH

AF:

0.342

Alfa

AF:

0.369

Hom.:

4659

Bravo

AF:

0.328

Asia WGS

AF:

0.350

AC:

1220

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.0090

DANN

Benign

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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