dbSNP rs2295639: MTHFD1:c.1495-171T>C (chr14-64435398-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005956.4(MTHFD1):c.1495-171T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.062 in 152,262 control chromosomes in the GnomAD database, including 516 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.062 ( 516 hom., cov: 31)

Consequence

MTHFD1
NM_005956.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.699

Publications

4 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 Gene-Disease associations (from GenCC):

combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

MTHFD1 links:

ENSG00000258824 (HGNC:):

ENSG00000258824 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFD1	NM_005956.4 link	c.1495-171T>C		intron_variant	Intron 15 of 27	ENST00000652337.1	NP_005947.3
MTHFD1	NM_001364837.1 link	c.1495-171T>C		intron_variant	Intron 15 of 26		NP_001351766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1 link	c.1495-171T>C		intron_variant	Intron 15 of 27		NM_005956.4	ENSP00000498336.1

Frequencies

GnomAD3 genomes

AF:

0.0619

AC:

9422

AN:

152144

Hom.:

513

Cov.:

show subpopulations

Gnomad AFR

AF:

0.156

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.0304

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.0168

Gnomad SAS

AF:

0.0168

Gnomad FIN

AF:

0.0178

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0284

Gnomad OTH

AF:

0.0525

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0620

AC:

9445

AN:

152262

Hom.:

516

Cov.:

AF XY:

0.0594

AC XY:

4423

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.156

AC:

6469

AN:

41534

American (AMR)

AF:

0.0302

AC:

463

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3470

East Asian (EAS)

AF:

0.0170

AC:

AN:

5180

South Asian (SAS)

AF:

0.0170

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0178

AC:

189

AN:

10614

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0283

AC:

1928

AN:

68018

Other (OTH)

AF:

0.0525

AC:

111

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

421

843

1264

1686

2107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<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:

0.0375

Hom.:

792

Bravo

AF:

0.0667

Asia WGS

AF:

0.0390

AC:

137

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.80

(source)

DANN

Benign

0.32

PhyloP100

-0.70

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over