rs2295639

Positions:

• chr14-64435398-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.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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.699

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
MTHFD1	NM_005956.4	c.1495-171T>C		intron_variant		ENST00000652337.1	NP_005947.3
MTHFD1	NM_001364837.1	c.1495-171T>C		intron_variant			NP_001351766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1	c.1495-171T>C		intron_variant			NM_005956.4	ENSP00000498336	P1
	ENST00000556640.1	n.506-12419A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0619 AC: 9422 AN: 152144 Hom.: 513 Cov.: 31

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.: 31 AF XY: 0.0594 AC XY: 4423 AN XY: 74452

Gnomad4 AFR AF: 0.156

Gnomad4 AMR AF: 0.0302

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.0170

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.0178

Gnomad4 NFE AF: 0.0283

Gnomad4 OTH AF: 0.0525

Alfa AF: 0.0319 Hom.: 289

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
DANN	Benign	0.32

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: rs2295639; hg19: chr14-64902116;