chr14-64459379-T-C

Variant names:

• chr14-64459379-T-C
• rs2281603
• NM_005956.4:c.*5-380T>C

Variant summary

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

The NM_005956.4(MTHFD1):​c.*5-380T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 152,152 control chromosomes in the GnomAD database, including 3,698 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 0.20 (3698 hom., cov: 32)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.182
• Publications: 26 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]

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFD1	NM_005956.4	c.*5-380T>C		intron_variant	Intron 27 of 27	ENST00000652337.1	NP_005947.3
MTHFD1	NM_001364837.1	c.2719-380T>C		intron_variant	Intron 26 of 26		NP_001351766.1
ZBTB25	NM_001304508.1	c.174-9741A>G		intron_variant	Intron 2 of 2		NP_001291437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1	c.*5-380T>C		intron_variant	Intron 27 of 27		NM_005956.4	ENSP00000498336.1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30666 AN: 152034 Hom.: 3700 Cov.: 32

Gnomad AFR AF: 0.0777

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.354

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.222

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

GnomAD4 genome AF: 0.202 AC: 30665 AN: 152152 Hom.: 3698 Cov.: 32 AF XY: 0.210 AC XY: 15607 AN XY: 74384

African (AFR) AF: 0.0775 AC: 3218 AN: 41530

American (AMR) AF: 0.216 AC: 3293 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 767 AN: 3472

East Asian (EAS) AF: 0.354 AC: 1834 AN: 5178

South Asian (SAS) AF: 0.226 AC: 1090 AN: 4818

European-Finnish (FIN) AF: 0.366 AC: 3869 AN: 10570

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.235 AC: 15951 AN: 67982

Other (OTH) AF: 0.220 AC: 466 AN: 2116

Alfa AF: 0.221 Hom.: 12189

Bravo AF: 0.187

Asia WGS AF: 0.262 AC: 913 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.67
PhyloP100		-0.18
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: rs2281603; hg19: chr14-64926097;