rs1256146

Positions:

• chr14-64453947-G-A

Variant summary

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

The NM_005956.4(MTHFD1):​c.2565+86G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 821,954 control chromosomes in the GnomAD database, including 13,510 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 0.17 (2360 hom., cov: 32)
  • Exomes 𝑓: 0.18 (11150 hom.)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.218

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]

ZBTB25 (HGNC:13112): (zinc finger and BTB domain containing 25) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MTHFD1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFD1	NM_005956.4	c.2565+86G>A		intron_variant		ENST00000652337.1	NP_005947.3
MTHFD1	NM_001364837.1	c.2565+86G>A		intron_variant			NP_001351766.1
ZBTB25	NM_001304508.1	c.174-4309C>T		intron_variant			NP_001291437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1	c.2565+86G>A		intron_variant			NM_005956.4	ENSP00000498336.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25892 AN: 151948 Hom.: 2355 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0876

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.199

GnomAD4 exome AF: 0.175 AC: 117498 AN: 669888 Hom.: 11150 AF XY: 0.177 AC XY: 63225 AN XY: 357182

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.178

Gnomad4 ASJ exome AF: 0.248

Gnomad4 EAS exome AF: 0.0881

Gnomad4 SAS exome AF: 0.182

Gnomad4 FIN exome AF: 0.0957

Gnomad4 NFE exome AF: 0.186

Gnomad4 OTH exome AF: 0.186

GnomAD4 genome AF: 0.170 AC: 25908 AN: 152066 Hom.: 2360 Cov.: 32 AF XY: 0.166 AC XY: 12343 AN XY: 74332

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.244

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.178

Gnomad4 FIN AF: 0.0876

Gnomad4 NFE AF: 0.186

Gnomad4 OTH AF: 0.197

Alfa AF: 0.184 Hom.: 705

Bravo AF: 0.180

Asia WGS AF: 0.150 AC: 521 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.41

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: rs1256146; hg19: chr14-64920665; COSMIC: COSV53700484; COSMIC: COSV53700484;