16-68122620-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_173165.3(NFATC3):c.737G>A(p.Arg246Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NFATC3 NM_173165.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFATC3	NM_173165.3	c.737G>A	p.Arg246Lys	missense_variant	2/10	ENST00000346183.8
NFATC3	NM_004555.4	c.737G>A	p.Arg246Lys	missense_variant	2/11
NFATC3	NM_173163.3	c.737G>A	p.Arg246Lys	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFATC3	ENST00000346183.8	c.737G>A	p.Arg246Lys	missense_variant	2/10	1	NM_173165.3	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

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

Jan 29, 2024

The c.737G>A (p.R246K) alteration is located in exon 2 (coding exon 2) of the NFATC3 gene. This alteration results from a G to A substitution at nucleotide position 737, causing the arginine (R) at amino acid position 246 to be replaced by a lysine (K). 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	Uncertain	0.35
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.47	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
Sift4G	Benign	0.074	T;T;T;T
Polyphen		1.0, 0.99	.;D;D;.
Vest4		0.60
MutPred		0.18		Gain of methylation at R246 (P = 0.0077);Gain of methylation at R246 (P = 0.0077);Gain of methylation at R246 (P = 0.0077);Gain of methylation at R246 (P = 0.0077);
MVP		0.45
MPC		0.42
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.56
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-68156523;