chr14-64456448-G-T

Position:

• chr14-64456448-G-T

Variant summary

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

The NM_005956.4(MTHFD1):​c.2718+1573G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 151,960 control chromosomes in the GnomAD database, including 7,420 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 0.31 (7420 hom., cov: 32)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0280

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFD1	NM_005956.4	c.2718+1573G>T		intron_variant		ENST00000652337.1
ZBTB25	NM_001304508.1	c.174-6810C>A		intron_variant
MTHFD1	NM_001364837.1	c.2718+1573G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD1	ENST00000652337.1	c.2718+1573G>T		intron_variant			NM_005956.4	P1

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47124 AN: 151842 Hom.: 7418 Cov.: 32

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.307

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

GnomAD4 genome AF: 0.310 AC: 47148 AN: 151960 Hom.: 7420 Cov.: 32 AF XY: 0.309 AC XY: 22983 AN XY: 74266

Gnomad4 AFR AF: 0.344

Gnomad4 AMR AF: 0.223

Gnomad4 ASJ AF: 0.294

Gnomad4 EAS AF: 0.419

Gnomad4 SAS AF: 0.255

Gnomad4 FIN AF: 0.305

Gnomad4 NFE AF: 0.308

Gnomad4 OTH AF: 0.307

Alfa AF: 0.308 Hom.: 914

Bravo AF: 0.305

Asia WGS AF: 0.336 AC: 1167 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.7
DANN	Benign	0.48

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: rs6573559; hg19: chr14-64923166;