ENST00000397790:c.-281C>G

Variant names:

• chr18-79396261-C-G
• rs1205294889
• ENST00000397790.6:c.-281C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000397790.6(NFATC1):​c.-281C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NFATC1 ENST00000397790.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.134
• Publications: 1 publications found

Genes affected

NFATC1 (HGNC:7775): (nuclear factor of activated T cells 1) The product of this gene is a component of the nuclear factor of activated T cells DNA-binding transcription complex. This complex consists of at least two components: a preexisting cytosolic component that translocates to the nucleus upon T cell receptor (TCR) stimulation, and an inducible nuclear component. Proteins belonging to this family of transcription factors play a central role in inducible gene transcription during immune response. The product of this gene is an inducible nuclear component. It functions as a major molecular target for the immunosuppressive drugs such as cyclosporin A. Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. Different isoforms of this protein may regulate inducible expression of different cytokine genes. [provided by RefSeq, Jul 2013]

NFATC1 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20731488).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397790.6. 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
	NFATC1	NM_001278669.2	MANE Select	c.37C>G	p.Pro13Ala	missense	Exon 1 of 10	NP_001265598.1	O95644-1
	NFATC1	NM_172388.3		c.-281C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_765976.1	O95644-17
	NFATC1	NM_006162.5		c.37C>G	p.Pro13Ala	missense	Exon 1 of 10	NP_006153.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFATC1	ENST00000397790.6	TSL:1	c.-281C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000380892.2	O95644-17
	NFATC1	ENST00000427363.7	TSL:1 MANE Select	c.37C>G	p.Pro13Ala	missense	Exon 1 of 10	ENSP00000389377.2	O95644-1
	NFATC1	ENST00000253506.9	TSL:1	c.37C>G	p.Pro13Ala	missense	Exon 1 of 10	ENSP00000253506.5	O95644-4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151520 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1337924 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 663592

African (AFR) AF: 0.00 AC: 0 AN: 27218

American (AMR) AF: 0.00 AC: 0 AN: 34100

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22348

East Asian (EAS) AF: 0.00 AC: 0 AN: 29226

South Asian (SAS) AF: 0.00 AC: 0 AN: 75258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4906

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1044102

Other (OTH) AF: 0.00 AC: 0 AN: 53434

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151520 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74012

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67806

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0092	T
Eigen	Benign	0.061
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.13
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.088	T
Polyphen		0.98	D
Vest4		0.15
MutPred		0.15		Loss of loop (P = 0.0288)
MVP		0.40
ClinPred		0.42	T
GERP RS		2.5
PromoterAI		-0.063	Neutral
Varity_R		0.22
gMVP		0.11
Mutation Taster		=82/18	polymorphism

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: rs1205294889; hg19: chr18-77156261;