18-79400428-T-C

Variant names:

• chr18-79400428-T-C
• rs371822461
• ENST00000329101.8:c.37T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_172387.3(NFATC1):​c.37T>C​(p.Phe13Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000893 in 1,343,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 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. F13I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: NFATC1 NM_172387.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.112
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25111002).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172387.3. 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.127+4077T>C		intron	N/A	NP_001265598.1	O95644-1
	NFATC1	NM_172387.3		c.37T>C	p.Phe13Leu	missense	Exon 1 of 10	NP_765975.1	O95644-6
	NFATC1	NM_172389.3		c.37T>C	p.Phe13Leu	missense	Exon 1 of 10	NP_765977.1	O95644-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFATC1	ENST00000329101.8	TSL:1	c.37T>C	p.Phe13Leu	missense	Exon 1 of 10	ENSP00000327850.3	O95644-6
	NFATC1	ENST00000318065.9	TSL:1	c.37T>C	p.Phe13Leu	missense	Exon 1 of 10	ENSP00000316553.5	O95644-5
	NFATC1	ENST00000592223.5	TSL:1	c.37T>C	p.Phe13Leu	missense	Exon 1 of 8	ENSP00000467181.1	O95644-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000893 AC: 12 AN: 1343520 Hom.: 0 Cov.: 35 AF XY: 0.00000603 AC XY: 4 AN XY: 663002

African (AFR) AF: 0.00 AC: 0 AN: 26966

American (AMR) AF: 0.00 AC: 0 AN: 28254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23328

East Asian (EAS) AF: 0.00 AC: 0 AN: 29164

South Asian (SAS) AF: 0.00 AC: 0 AN: 74066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5500

European-Non Finnish (NFE) AF: 0.0000114 AC: 12 AN: 1054144

Other (OTH) AF: 0.00 AC: 0 AN: 55110

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	20
DANN	Uncertain	0.98
Eigen	Benign	-0.014
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.79	T
PhyloP100		0.11
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	0.50	N
REVEL	Benign	0.12
Sift	Benign	0.37	T
Sift4G	Benign	1.0	T
Vest4		0.43
MutPred		0.36		Gain of helix (P = 0.132)
MVP		0.34
MPC		0.34
ClinPred		0.88	D
GERP RS		3.4
PromoterAI		-0.092	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=290/10	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: rs371822461; hg19: chr18-77160428;