chr14-64420993-G-A

Variant names:

• chr14-64420993-G-A
• rs17824591
• NM_005956.4:c.727+1068G>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.727+1068G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 152,138 control chromosomes in the GnomAD database, including 2,224 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 0.15 (2224 hom., cov: 32)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.707
• Publications: 18 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.211 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.727+1068G>A		intron	N/A	NP_005947.3
	MTHFD1	NM_001364837.1		c.727+1068G>A		intron	N/A	NP_001351766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1	ENST00000652337.1	MANE Select	c.727+1068G>A		intron	N/A	ENSP00000498336.1
	MTHFD1	ENST00000555252.5	TSL:1	n.784+1068G>A		intron	N/A
	MTHFD1	ENST00000652503.1		n.710G>A		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23330 AN: 152020 Hom.: 2224 Cov.: 32

Gnomad AFR AF: 0.0588

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.163

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

GnomAD4 genome AF: 0.153 AC: 23333 AN: 152138 Hom.: 2224 Cov.: 32 AF XY: 0.151 AC XY: 11209 AN XY: 74354

African (AFR) AF: 0.0587 AC: 2438 AN: 41530

American (AMR) AF: 0.142 AC: 2173 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 743 AN: 3468

East Asian (EAS) AF: 0.0234 AC: 121 AN: 5182

South Asian (SAS) AF: 0.147 AC: 708 AN: 4812

European-Finnish (FIN) AF: 0.185 AC: 1949 AN: 10558

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14547 AN: 68000

Other (OTH) AF: 0.161 AC: 341 AN: 2114

Alfa AF: 0.185 Hom.: 4812

Bravo AF: 0.145

Asia WGS AF: 0.0940 AC: 326 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.75
DANN	Benign	0.73
PhyloP100		-0.71
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: rs17824591; hg19: chr14-64887711;