14-64444909-T-C

Position:

• chr14-64444909-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005956.4(MTHFD1):​c.2178+175T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.928 in 675,236 control chromosomes in the GnomAD database, including 291,517 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 0.90 (62430 hom., cov: 31)
  • Exomes 𝑓: 0.94 (229087 hom.)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.937 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFD1	NM_005956.4	c.2178+175T>C		intron_variant		ENST00000652337.1	NP_005947.3
MTHFD1	NM_001364837.1	c.2178+175T>C		intron_variant			NP_001351766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFD1	ENST00000652337.1	c.2178+175T>C		intron_variant			NM_005956.4	ENSP00000498336	P1
	ENST00000556640.1	n.505+3144A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.904 AC: 137423 AN: 152088 Hom.: 62396 Cov.: 31

Gnomad AFR AF: 0.805

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.949

Gnomad ASJ AF: 0.945

Gnomad EAS AF: 0.951

Gnomad SAS AF: 0.906

Gnomad FIN AF: 0.927

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.943

Gnomad OTH AF: 0.925

GnomAD4 exome AF: 0.935 AC: 489188 AN: 523030 Hom.: 229087 Cov.: 6 AF XY: 0.935 AC XY: 263097 AN XY: 281500

Gnomad4 AFR exome AF: 0.802

Gnomad4 AMR exome AF: 0.957

Gnomad4 ASJ exome AF: 0.949

Gnomad4 EAS exome AF: 0.944

Gnomad4 SAS exome AF: 0.903

Gnomad4 FIN exome AF: 0.925

Gnomad4 NFE exome AF: 0.946

Gnomad4 OTH exome AF: 0.931

GnomAD4 genome AF: 0.903 AC: 137516 AN: 152206 Hom.: 62430 Cov.: 31 AF XY: 0.904 AC XY: 67262 AN XY: 74418

Gnomad4 AFR AF: 0.805

Gnomad4 AMR AF: 0.949

Gnomad4 ASJ AF: 0.945

Gnomad4 EAS AF: 0.951

Gnomad4 SAS AF: 0.906

Gnomad4 FIN AF: 0.927

Gnomad4 NFE AF: 0.943

Gnomad4 OTH AF: 0.926

Alfa AF: 0.912 Hom.: 13892

Bravo AF: 0.902

Asia WGS AF: 0.925 AC: 3217 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs1256143; hg19: chr14-64911627;