chr14-64401953-T-C

Variant names:

• chr14-64401953-T-C
• rs8006686
• NM_005956.4:c.126+1076T>C

Variant summary

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

The NM_005956.4(MTHFD1):​c.126+1076T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,132 control chromosomes in the GnomAD database, including 3,987 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 0.21 (3987 hom., cov: 33)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.12
• Publications: 6 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]

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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFD1	NM_005956.4	c.126+1076T>C		intron_variant	Intron 2 of 27	ENST00000652337.1	NP_005947.3
MTHFD1	NM_001364837.1	c.126+1076T>C		intron_variant	Intron 2 of 26		NP_001351766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1	c.126+1076T>C		intron_variant	Intron 2 of 27		NM_005956.4	ENSP00000498336.1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32628 AN: 152014 Hom.: 3978 Cov.: 33

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.208

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

GnomAD4 genome AF: 0.215 AC: 32671 AN: 152132 Hom.: 3987 Cov.: 33 AF XY: 0.211 AC XY: 15706 AN XY: 74386

African (AFR) AF: 0.334 AC: 13829 AN: 41452

American (AMR) AF: 0.187 AC: 2860 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 807 AN: 3468

East Asian (EAS) AF: 0.144 AC: 746 AN: 5186

South Asian (SAS) AF: 0.172 AC: 828 AN: 4822

European-Finnish (FIN) AF: 0.129 AC: 1371 AN: 10602

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11506 AN: 68020

Other (OTH) AF: 0.206 AC: 435 AN: 2112

Alfa AF: 0.199 Hom.: 1106

Bravo AF: 0.224

Asia WGS AF: 0.166 AC: 579 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.70
PhyloP100		-2.1
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: rs8006686; hg19: chr14-64868671;