chr14-64388323-T-C

Variant names:

• chr14-64388323-T-C
• rs1076991
• ENST00000555252.5:n.13T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000545908.6(MTHFD1):​c.-105T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 1,610,458 control chromosomes in the GnomAD database, including 175,153 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 0.54 (24417 hom., cov: 33)
  • Exomes 𝑓: 0.45 (150736 hom.)
• Consequence: MTHFD1 ENST00000545908.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.92
• Publications: 49 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)

ENSG00000293482 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0874219E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000545908.6. 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.-105T>C		upstream_gene	N/A	NP_005947.3
	MTHFD1	NM_001364837.1		c.-105T>C		upstream_gene	N/A	NP_001351766.1	F5H2F4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFD1	ENST00000555252.5	TSL:1	n.13T>C		non_coding_transcript_exon	Exon 1 of 17
	MTHFD1	ENST00000545908.6	TSL:2	c.-105T>C		5_prime_UTR	Exon 1 of 27	ENSP00000438588.2	F5H2F4
	MTHFD1	ENST00000940490.1		c.-105T>C		5_prime_UTR	Exon 1 of 28	ENSP00000610549.1

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81667 AN: 152006 Hom.: 24378 Cov.: 33

Gnomad AFR AF: 0.814

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.529

GnomAD2 exomes AF: 0.453 AC: 112290 AN: 248014 AF XY: 0.446

Gnomad AFR exome AF: 0.818

Gnomad AMR exome AF: 0.458

Gnomad ASJ exome AF: 0.557

Gnomad EAS exome AF: 0.257

Gnomad FIN exome AF: 0.337

Gnomad NFE exome AF: 0.449

Gnomad OTH exome AF: 0.440

GnomAD4 exome AF: 0.448 AC: 653027 AN: 1458334 Hom.: 150736 Cov.: 46 AF XY: 0.446 AC XY: 323420 AN XY: 724888

African (AFR) AF: 0.832 AC: 27805 AN: 33414

American (AMR) AF: 0.457 AC: 20338 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 14525 AN: 26032

East Asian (EAS) AF: 0.234 AC: 9269 AN: 39624

South Asian (SAS) AF: 0.433 AC: 37260 AN: 86068

European-Finnish (FIN) AF: 0.345 AC: 18326 AN: 53164

Middle Eastern (MID) AF: 0.478 AC: 2750 AN: 5752

European-Non Finnish (NFE) AF: 0.446 AC: 495068 AN: 1109568

Other (OTH) AF: 0.460 AC: 27686 AN: 60228

GnomAD4 genome AF: 0.537 AC: 81763 AN: 152124 Hom.: 24417 Cov.: 33 AF XY: 0.527 AC XY: 39156 AN XY: 74364

African (AFR) AF: 0.814 AC: 33790 AN: 41526

American (AMR) AF: 0.468 AC: 7136 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1954 AN: 3472

East Asian (EAS) AF: 0.242 AC: 1251 AN: 5176

South Asian (SAS) AF: 0.417 AC: 2008 AN: 4810

European-Finnish (FIN) AF: 0.336 AC: 3554 AN: 10586

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30322 AN: 67982

Other (OTH) AF: 0.523 AC: 1103 AN: 2108

Alfa AF: 0.475 Hom.: 24697

Bravo AF: 0.560

TwinsUK AF: 0.448 AC: 1663

ALSPAC AF: 0.434 AC: 1674

ExAC AF: 0.459 AC: 55710

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.25
DANN	Benign	0.41
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.027	N
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.9
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.0050
Sift	Benign	0.031	D
Sift4G	Uncertain	0.029	D
Polyphen		0.0	B
Vest4		0.098
MutPred		0.27		Gain of disorder (P = 0.0017)
ClinPred		0.030	T
GERP RS		-9.3
PromoterAI		0.038	Neutral
Mutation Taster		=98/2	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1076991; hg19: chr14-64855041; COSMIC: COSV53697561; COSMIC: COSV53697561;