rs10498514

Variant names:

• chr14-64432337-A-C
• rs10498514
• NM_005956.4:c.1494+476A>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.1494+476A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0711 in 152,278 control chromosomes in the GnomAD database, including 746 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 0.071 (746 hom., cov: 32)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0820
• Publications: 13 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFD1	NM_005956.4	c.1494+476A>C		intron_variant	Intron 15 of 27	ENST00000652337.1	NP_005947.3
MTHFD1	NM_001364837.1	c.1494+476A>C		intron_variant	Intron 15 of 26		NP_001351766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1	c.1494+476A>C		intron_variant	Intron 15 of 27		NM_005956.4	ENSP00000498336.1

Frequencies

GnomAD3 genomes AF: 0.0710 AC: 10805 AN: 152160 Hom.: 743 Cov.: 32

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.0626

Gnomad AMR AF: 0.0327

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.0167

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0587

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

GnomAD4 genome AF: 0.0711 AC: 10829 AN: 152278 Hom.: 746 Cov.: 32 AF XY: 0.0680 AC XY: 5063 AN XY: 74468

African (AFR) AF: 0.188 AC: 7806 AN: 41528

American (AMR) AF: 0.0326 AC: 498 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3472

East Asian (EAS) AF: 0.0169 AC: 88 AN: 5192

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4824

European-Finnish (FIN) AF: 0.0181 AC: 192 AN: 10620

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0283 AC: 1925 AN: 68030

Other (OTH) AF: 0.0586 AC: 124 AN: 2116

Alfa AF: 0.0402 Hom.: 1120

Bravo AF: 0.0774

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.55
DANN	Benign	0.46
PhyloP100		-0.082
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: rs10498514; hg19: chr14-64899055;