14-64456448-G-T

Variant names:

• chr14-64456448-G-T
• rs6573559
• NM_005956.4:c.2718+1573G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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=-0.94).
• 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 rank	MANE	Protein	UniProt
MTHFD1	NM_005956.4	c.2718+1573G>T		intron_variant	Intron 26 of 27	ENST00000652337.1	NP_005947.3
MTHFD1	NM_001364837.1	c.2718+1573G>T		intron_variant	Intron 26 of 26		NP_001351766.1
ZBTB25	NM_001304508.1	c.174-6810C>A		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.2718+1573G>T		intron_variant	Intron 26 of 27		NM_005956.4	ENSP00000498336.1

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

African (AFR) AF: 0.344 AC: 14231 AN: 41410

American (AMR) AF: 0.223 AC: 3408 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1020 AN: 3466

East Asian (EAS) AF: 0.419 AC: 2167 AN: 5176

South Asian (SAS) AF: 0.255 AC: 1230 AN: 4820

European-Finnish (FIN) AF: 0.305 AC: 3215 AN: 10534

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.308 AC: 20962 AN: 67968

Other (OTH) AF: 0.307 AC: 650 AN: 2114

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
PhyloP100		-0.028
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: rs6573559; hg19: chr14-64923166;