14-64436730-T-C

Variant names:

• chr14-64436730-T-C
• rs8016556
• NM_005956.4:c.1597+1059T>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.1597+1059T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 152,116 control chromosomes in the GnomAD database, including 7,826 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 0.31 (7826 hom., cov: 32)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.61
• Publications: 15 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)

ENSG00000258824 (HGNC:):

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 (EAS) allele frequency at 95% confidence interval = 0.568 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.1597+1059T>C		intron	N/A	NP_005947.3
	MTHFD1	NM_001364837.1		c.1597+1059T>C		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.1597+1059T>C		intron	N/A	ENSP00000498336.1
	MTHFD1	ENST00000555252.5	TSL:1	n.1654+1059T>C		intron	N/A
	MTHFD1	ENST00000545908.6	TSL:2	c.1597+1059T>C		intron	N/A	ENSP00000438588.2

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47545 AN: 152000 Hom.: 7829 Cov.: 32

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.307

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

GnomAD4 genome AF: 0.313 AC: 47566 AN: 152116 Hom.: 7826 Cov.: 32 AF XY: 0.316 AC XY: 23520 AN XY: 74360

African (AFR) AF: 0.238 AC: 9881 AN: 41478

American (AMR) AF: 0.250 AC: 3819 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1106 AN: 3468

East Asian (EAS) AF: 0.586 AC: 3033 AN: 5178

South Asian (SAS) AF: 0.278 AC: 1339 AN: 4822

European-Finnish (FIN) AF: 0.390 AC: 4122 AN: 10578

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23246 AN: 67984

Other (OTH) AF: 0.308 AC: 650 AN: 2108

Alfa AF: 0.330 Hom.: 4420

Bravo AF: 0.300

Asia WGS AF: 0.408 AC: 1420 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.22
DANN	Benign	0.33
PhyloP100		-1.6
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: rs8016556; hg19: chr14-64903448;