rs56811449

Variant names:

• chr14-64417358-C-T
• rs56811449
• NM_005956.4:c.479-530C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005956.4(MTHFD1):​c.479-530C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,180 control chromosomes in the GnomAD database, including 2,004 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 0.16 (2004 hom., cov: 32)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.388
• Publications: 3 publications found

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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFD1	NM_005956.4	c.479-530C>T		intron_variant	Intron 6 of 27	ENST00000652337.1	NP_005947.3
MTHFD1	NM_001364837.1	c.479-530C>T		intron_variant	Intron 6 of 26		NP_001351766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1	c.479-530C>T		intron_variant	Intron 6 of 27		NM_005956.4	ENSP00000498336.1

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24093 AN: 152062 Hom.: 2005 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0788

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.181

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

GnomAD4 genome AF: 0.158 AC: 24114 AN: 152180 Hom.: 2004 Cov.: 32 AF XY: 0.154 AC XY: 11461 AN XY: 74382

African (AFR) AF: 0.186 AC: 7704 AN: 41506

American (AMR) AF: 0.138 AC: 2110 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 768 AN: 3466

East Asian (EAS) AF: 0.107 AC: 554 AN: 5182

South Asian (SAS) AF: 0.124 AC: 597 AN: 4820

European-Finnish (FIN) AF: 0.0788 AC: 835 AN: 10592

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10940 AN: 68008

Other (OTH) AF: 0.179 AC: 379 AN: 2112

Alfa AF: 0.167 Hom.: 1276

Bravo AF: 0.164

Asia WGS AF: 0.109 AC: 379 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.5
DANN	Benign	0.73
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56811449; hg19: chr14-64884076;