18-79467476-A-C

Variant names:

• chr18-79467476-A-C
• rs25656
• ENST00000587635.5:c.1901A>C

Variant summary

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

The ENST00000587635.5(NFATC1):​c.1901A>C​(p.His634Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H634R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFATC1 ENST00000587635.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.08
• Publications: 14 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=0.070727766).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000587635.5. 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
	NFATC1	NM_001278669.2	MANE Select	c.1986A>C	p.Pro662Pro	synonymous	Exon 8 of 10	NP_001265598.1
	NFATC1	NM_172387.3		c.1947A>C	p.Pro649Pro	synonymous	Exon 8 of 10	NP_765975.1
	NFATC1	NM_006162.5		c.1986A>C	p.Pro662Pro	synonymous	Exon 8 of 10	NP_006153.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFATC1	ENST00000587635.5	TSL:1	c.1901A>C	p.His634Pro	missense	Exon 8 of 8	ENSP00000468111.1
	NFATC1	ENST00000427363.7	TSL:1 MANE Select	c.1986A>C	p.Pro662Pro	synonymous	Exon 8 of 10	ENSP00000389377.2
	NFATC1	ENST00000329101.8	TSL:1	c.1947A>C	p.Pro649Pro	synonymous	Exon 8 of 10	ENSP00000327850.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 23247

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.016
DANN	Benign	0.29
DEOGEN2	Benign	0.0069	T
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.071	T
PhyloP100		-4.1
Vest4		0.10
MVP		0.41
GERP RS		-9.4
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs25656; hg19: chr18-77227476;