chr14-64435398-T-C

Variant names:

• chr14-64435398-T-C
• rs2295639
• NM_005956.4:c.1495-171T>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.1495-171T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.062 in 152,262 control chromosomes in the GnomAD database, including 516 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 0.062 (516 hom., cov: 31)
• Consequence: MTHFD1 NM_005956.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.699
• Publications: 4 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 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.1495-171T>C		intron	N/A	NP_005947.3
	MTHFD1	NM_001364837.1		c.1495-171T>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.1495-171T>C		intron	N/A	ENSP00000498336.1
	MTHFD1	ENST00000555252.5	TSL:1	n.1552-171T>C		intron	N/A
	MTHFD1	ENST00000545908.6	TSL:2	c.1495-171T>C		intron	N/A	ENSP00000438588.2

Frequencies

GnomAD3 genomes AF: 0.0619 AC: 9422 AN: 152144 Hom.: 513 Cov.: 31

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0304

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.0168

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.0178

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0525

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

GnomAD4 genome AF: 0.0620 AC: 9445 AN: 152262 Hom.: 516 Cov.: 31 AF XY: 0.0594 AC XY: 4423 AN XY: 74452

African (AFR) AF: 0.156 AC: 6469 AN: 41534

American (AMR) AF: 0.0302 AC: 463 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3470

East Asian (EAS) AF: 0.0170 AC: 88 AN: 5180

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4818

European-Finnish (FIN) AF: 0.0178 AC: 189 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0283 AC: 1928 AN: 68018

Other (OTH) AF: 0.0525 AC: 111 AN: 2116

Alfa AF: 0.0375 Hom.: 792

Bravo AF: 0.0667

Asia WGS AF: 0.0390 AC: 137 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.80
DANN	Benign	0.32
PhyloP100		-0.70
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: rs2295639; hg19: chr14-64902116;