16-68157883-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173165.3(NFATC3):c.1416C>G(p.Asn472Lys) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFATC3 NM_173165.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0140

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16745403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFATC3	NM_173165.3	c.1416C>G	p.Asn472Lys	missense_variant	4/10	ENST00000346183.8
NFATC3	NM_004555.4	c.1416C>G	p.Asn472Lys	missense_variant	4/11
NFATC3	NM_173163.3	c.1416C>G	p.Asn472Lys	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFATC3	ENST00000346183.8	c.1416C>G	p.Asn472Lys	missense_variant	4/10	1	NM_173165.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Oct 20, 2021

The c.1416C>G (p.N472K) alteration is located in exon 4 (coding exon 4) of the NFATC3 gene. This alteration results from a C to G substitution at nucleotide position 1416, causing the asparagine (N) at amino acid position 472 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	0.39
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	15
Dann	Benign	0.97
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.58	T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.91	D;D;D;D
PrimateAI	Benign	0.38	T
Sift4G	Benign	0.53	T;T;T;T
Polyphen		0.27, 0.038	.;B;B;.
Vest4		0.31
MutPred		0.50		Gain of ubiquitination at N472 (P = 0.0351);Gain of ubiquitination at N472 (P = 0.0351);Gain of ubiquitination at N472 (P = 0.0351);Gain of ubiquitination at N472 (P = 0.0351);
MVP		0.47
MPC		0.12
ClinPred		0.17	T
GERP RS		2.7
Varity_R		0.081
gMVP		0.24

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: chr16-68191786;