14-64444909-T-C

Variant names:

• chr14-64444909-T-C
• rs1256143
• NM_005956.4:c.2178+175T>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.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
• Publications: 7 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.937 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1	NM_005956.4	MANE Select	c.2178+175T>C		intron	N/A	NP_005947.3
	MTHFD1	NM_001364837.1		c.2178+175T>C		intron	N/A	NP_001351766.1	F5H2F4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1	ENST00000652337.1	MANE Select	c.2178+175T>C		intron	N/A	ENSP00000498336.1	P11586
	MTHFD1	ENST00000545908.6	TSL:2	c.2178+175T>C		intron	N/A	ENSP00000438588.2	F5H2F4
	MTHFD1	ENST00000900031.1		c.2259+175T>C		intron	N/A	ENSP00000570090.1

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

African (AFR) AF: 0.802 AC: 11923 AN: 14860

American (AMR) AF: 0.957 AC: 30360 AN: 31712

Ashkenazi Jewish (ASJ) AF: 0.949 AC: 16131 AN: 17000

East Asian (EAS) AF: 0.944 AC: 29074 AN: 30796

South Asian (SAS) AF: 0.903 AC: 51210 AN: 56680

European-Finnish (FIN) AF: 0.925 AC: 31598 AN: 34172

Middle Eastern (MID) AF: 0.895 AC: 2079 AN: 2322

European-Non Finnish (NFE) AF: 0.946 AC: 290248 AN: 306944

Other (OTH) AF: 0.931 AC: 26565 AN: 28544

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

African (AFR) AF: 0.805 AC: 33403 AN: 41488

American (AMR) AF: 0.949 AC: 14532 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.945 AC: 3278 AN: 3470

East Asian (EAS) AF: 0.951 AC: 4924 AN: 5178

South Asian (SAS) AF: 0.906 AC: 4373 AN: 4826

European-Finnish (FIN) AF: 0.927 AC: 9836 AN: 10612

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.943 AC: 64142 AN: 68010

Other (OTH) AF: 0.926 AC: 1952 AN: 2108

Alfa AF: 0.900 Hom.: 39572

Bravo AF: 0.902

Asia WGS AF: 0.925 AC: 3217 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.41
PhyloP100		-1.7
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: rs1256143; hg19: chr14-64911627;