rs56811449

Positions:

• chr14-64417358-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
MTHFD1	NM_005956.4	c.479-530C>T		intron_variant		ENST00000652337.1
MTHFD1	NM_001364837.1	c.479-530C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD1	ENST00000652337.1	c.479-530C>T		intron_variant			NM_005956.4	P1

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

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.107

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.0788

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.179

Alfa AF: 0.160 Hom.: 434

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

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

Other links and lift over

dbSNP: rs56811449; hg19: chr14-64884076;