rs1256146

Variant names:

• chr14-64453947-G-A
• rs1256146
• NM_005956.4:c.2565+86G>A

Variant summary

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

The NM_005956.4(MTHFD1):​c.2565+86G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 821,954 control chromosomes in the GnomAD database, including 13,510 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 0.17 (2360 hom., cov: 32)
  • Exomes 𝑓: 0.18 (11150 hom.)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.218
• Publications: 22 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFD1	NM_005956.4	c.2565+86G>A		intron_variant	Intron 25 of 27	ENST00000652337.1	NP_005947.3
MTHFD1	NM_001364837.1	c.2565+86G>A		intron_variant	Intron 25 of 26		NP_001351766.1
ZBTB25	NM_001304508.1	c.174-4309C>T		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.2565+86G>A		intron_variant	Intron 25 of 27		NM_005956.4	ENSP00000498336.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25892 AN: 151948 Hom.: 2355 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0876

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.199

GnomAD4 exome AF: 0.175 AC: 117498 AN: 669888 Hom.: 11150 AF XY: 0.177 AC XY: 63225 AN XY: 357182

African (AFR) AF: 0.162 AC: 2814 AN: 17332

American (AMR) AF: 0.178 AC: 6530 AN: 36616

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 5116 AN: 20588

East Asian (EAS) AF: 0.0881 AC: 2859 AN: 32464

South Asian (SAS) AF: 0.182 AC: 11885 AN: 65210

European-Finnish (FIN) AF: 0.0957 AC: 4732 AN: 49430

Middle Eastern (MID) AF: 0.254 AC: 1080 AN: 4246

European-Non Finnish (NFE) AF: 0.186 AC: 76172 AN: 410002

Other (OTH) AF: 0.186 AC: 6310 AN: 34000

GnomAD4 genome AF: 0.170 AC: 25908 AN: 152066 Hom.: 2360 Cov.: 32 AF XY: 0.166 AC XY: 12343 AN XY: 74332

African (AFR) AF: 0.161 AC: 6682 AN: 41468

American (AMR) AF: 0.184 AC: 2811 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 847 AN: 3470

East Asian (EAS) AF: 0.104 AC: 537 AN: 5172

South Asian (SAS) AF: 0.178 AC: 854 AN: 4800

European-Finnish (FIN) AF: 0.0876 AC: 927 AN: 10580

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12643 AN: 67986

Other (OTH) AF: 0.197 AC: 416 AN: 2112

Alfa AF: 0.184 Hom.: 1612

Bravo AF: 0.180

Asia WGS AF: 0.150 AC: 521 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.41
PhyloP100		0.22
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: rs1256146; hg19: chr14-64920665; COSMIC: COSV53700484; COSMIC: COSV53700484;