16-68122988-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_173165.3(NFATC3):c.1105C>T(p.Arg369Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000185 in 1,614,052 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R369Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: NFATC3 NM_173165.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.72

Genes affected

NFATC3 (HGNC:7777): (nuclear factor of activated T cells 3) The product of this gene is a member of the nuclear factors 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. Other members of this family participate to form this complex also. The product of this gene plays a role in the regulation of gene expression in T cells and immature thymocytes. Several transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.079595715).
• BS2: High AC in GnomAd at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFATC3	NM_173165.3	c.1105C>T	p.Arg369Trp	missense_variant	2/10	ENST00000346183.8
NFATC3	NM_004555.4	c.1105C>T	p.Arg369Trp	missense_variant	2/11
NFATC3	NM_173163.3	c.1105C>T	p.Arg369Trp	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFATC3	ENST00000346183.8	c.1105C>T	p.Arg369Trp	missense_variant	2/10	1	NM_173165.3	P3

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152102 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000346 AC: 87 AN: 251292 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135830

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.000510

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000191 AC: 279 AN: 1461832 Hom.: 0 Cov.: 35 AF XY: 0.000162 AC XY: 118 AN XY: 727218

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.000175

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152220 Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10 AN XY: 74412

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000169 Hom.: 1

Bravo AF: 0.000121

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000527 AC: 64

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.1105C>T (p.R369W) alteration is located in exon 2 (coding exon 2) of the NFATC3 gene. This alteration results from a C to T substitution at nucleotide position 1105, causing the arginine (R) at amino acid position 369 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.41
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.080	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Benign	0.45	T
Sift4G	Uncertain	0.019	D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.37
MVP		0.15
MPC		0.24
ClinPred		0.77	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.081
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs142644036; hg19: chr16-68156891; COSMIC: COSV60474154; COSMIC: COSV60474154;