rs11849530

Variant names:

• chr14-64451694-A-G
• rs11849530
• NM_005956.4:c.2458-2060A>G

Variant summary

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

The NM_005956.4(MTHFD1):​c.2458-2060A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 152,140 control chromosomes in the GnomAD database, including 3,742 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 (3742 hom., cov: 32)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.422
• Publications: 16 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=-0.7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005956.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1	NM_005956.4	MANE Select	c.2458-2060A>G		intron	N/A	NP_005947.3
	MTHFD1	NM_001364837.1		c.2458-2060A>G		intron	N/A	NP_001351766.1
	ZBTB25	NM_001304508.1		c.174-2056T>C		intron	N/A	NP_001291437.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1	ENST00000652337.1	MANE Select	c.2458-2060A>G		intron	N/A	ENSP00000498336.1
	ZBTB25	ENST00000555220.5	TSL:1	c.174-2056T>C		intron	N/A	ENSP00000450718.1
	MTHFD1	ENST00000545908.6	TSL:2	c.2458-2060A>G		intron	N/A	ENSP00000438588.2

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30975 AN: 152022 Hom.: 3744 Cov.: 32

Gnomad AFR AF: 0.0818

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.224

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

GnomAD4 genome AF: 0.204 AC: 30973 AN: 152140 Hom.: 3742 Cov.: 32 AF XY: 0.212 AC XY: 15735 AN XY: 74354

African (AFR) AF: 0.0816 AC: 3390 AN: 41556

American (AMR) AF: 0.220 AC: 3366 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 776 AN: 3470

East Asian (EAS) AF: 0.353 AC: 1813 AN: 5142

South Asian (SAS) AF: 0.228 AC: 1101 AN: 4830

European-Finnish (FIN) AF: 0.365 AC: 3853 AN: 10548

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

European-Non Finnish (NFE) AF: 0.236 AC: 16028 AN: 67986

Other (OTH) AF: 0.222 AC: 469 AN: 2110

Alfa AF: 0.202 Hom.: 456

Bravo AF: 0.190

Asia WGS AF: 0.263 AC: 916 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.33
DANN	Benign	0.82
PhyloP100		-0.42
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: rs11849530; hg19: chr14-64918412;