rs34616731

Variant names:

• chr14-64462569-T-A
• rs34616731
• ENST00000555220.5:c.174-12931A>T

Variant summary

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

The ENST00000555220.5(ZBTB25):​c.174-12931A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 152,184 control chromosomes in the GnomAD database, including 2,548 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 0.18 (2548 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZBTB25 ENST00000555220.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.183
• Publications: 6 publications found

Genes affected

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: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]

MTHFD1 Gene-Disease associations (from GenCC):

• combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB25	NM_001304508.1	c.174-12931A>T		intron_variant	Intron 2 of 2		NP_001291437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB25	ENST00000555220.5	c.174-12931A>T		intron_variant	Intron 2 of 2	1		ENSP00000450718.1
MTHFD1	ENST00000545908.6	c.*2634T>A		3_prime_UTR_variant	Exon 27 of 27	2		ENSP00000438588.2
ZBTB25	ENST00000555424.1	c.257-12931A>T		intron_variant	Intron 2 of 2	5		ENSP00000451046.1

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27045 AN: 152064 Hom.: 2540 Cov.: 31

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.0873

Gnomad MID AF: 0.274

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.209

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 14 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 10

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 10

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.178 AC: 27079 AN: 152184 Hom.: 2548 Cov.: 31 AF XY: 0.173 AC XY: 12861 AN XY: 74408

African (AFR) AF: 0.186 AC: 7720 AN: 41496

American (AMR) AF: 0.186 AC: 2839 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 847 AN: 3468

East Asian (EAS) AF: 0.123 AC: 635 AN: 5178

South Asian (SAS) AF: 0.168 AC: 807 AN: 4816

European-Finnish (FIN) AF: 0.0873 AC: 926 AN: 10604

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12677 AN: 68002

Other (OTH) AF: 0.207 AC: 438 AN: 2116

Alfa AF: 0.179 Hom.: 320

Bravo AF: 0.189

Asia WGS AF: 0.163 AC: 568 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.0
DANN	Benign	0.90
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34616731; hg19: chr14-64929287;