rs8006686

Positions:

• chr14-64401953-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005956.4(MTHFD1):​c.126+1076T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,132 control chromosomes in the GnomAD database, including 3,987 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 0.21 (3987 hom., cov: 33)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.12

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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFD1	NM_005956.4	c.126+1076T>C		intron_variant		ENST00000652337.1
MTHFD1	NM_001364837.1	c.126+1076T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD1	ENST00000652337.1	c.126+1076T>C		intron_variant			NM_005956.4	P1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32628 AN: 152014 Hom.: 3978 Cov.: 33

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.208

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

GnomAD4 genome AF: 0.215 AC: 32671 AN: 152132 Hom.: 3987 Cov.: 33 AF XY: 0.211 AC XY: 15706 AN XY: 74386

Gnomad4 AFR AF: 0.334

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.233

Gnomad4 EAS AF: 0.144

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.206

Alfa AF: 0.201 Hom.: 598

Bravo AF: 0.224

Asia WGS AF: 0.166 AC: 579 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.70

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: rs8006686; hg19: chr14-64868671;