14-64387955-A-G

Variant names:

• chr14-64387955-A-G
• rs746488
• ENST00000641479.1:n.32T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000641479.1(ENSG00000293482):​n.32T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENSG00000293482 ENST00000641479.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.236
• Publications: 1 publications found

Genes affected

ENSG00000293482 (HGNC:):

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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000641479.1. 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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000293482	ENST00000641479.1		n.32T>C		non_coding_transcript_exon	Exon 1 of 7
	ENSG00000293482	ENST00000689962.2		n.25T>C		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000293482	ENST00000771650.1		n.149T>C		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 167420 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 84870

African (AFR) AF: 0.00 AC: 0 AN: 5570

American (AMR) AF: 0.00 AC: 0 AN: 6300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6158

East Asian (EAS) AF: 0.00 AC: 0 AN: 14894

South Asian (SAS) AF: 0.00 AC: 0 AN: 5134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 900

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 105744

Other (OTH) AF: 0.00 AC: 0 AN: 10828

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.5
DANN	Benign	0.46
PhyloP100		0.24
PromoterAI		0.024	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746488; hg19: chr14-64854673;