14-24368413-C-G

Position:

• chr14-24368413-C-G

Variant summary

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

The NM_004554.5(NFATC4):​c.73C>G​(p.Pro25Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,348,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. P25T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: NFATC4 NM_004554.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.68

Genes affected

NFATC4 (HGNC:7778): (nuclear factor of activated T cells 4) This gene encodes a member of the nuclear factor of activated T cells (NFAT) protein family. The encoded protein is part of a 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 stimulation and an inducible nuclear component. NFAT proteins are activated by the calmodulin-dependent phosphatase, calcineurin. The encoded protein plays a role in the inducible expression of cytokine genes in T cells, especially in the induction of interleukin-2 and interleukin-4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

LOC124903291 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21276951).
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFATC4	NM_004554.5	c.73C>G	p.Pro25Ala	missense_variant	1/10	ENST00000250373.9
LOC124903291	XR_007064085.1	n.139+834G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFATC4	ENST00000250373.9	c.73C>G	p.Pro25Ala	missense_variant	1/10	1	NM_004554.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151906 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 9 AN: 1196126 Hom.: 0 Cov.: 34 AF XY: 0.0000104 AC XY: 6 AN XY: 574946

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000612

Gnomad4 OTH exome AF: 0.0000620

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151906 Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1 AN XY: 74172

Gnomad4 AFR AF: 0.0000967

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000529

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

Mar 01, 2023

The c.73C>G (p.P25A) alteration is located in exon 1 (coding exon 1) of the NFATC4 gene. This alteration results from a C to G substitution at nucleotide position 73, causing the proline (P) at amino acid position 25 to be replaced by an alanine (A). 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	0.052
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	.;.;.;.;.;.;.;.;.;T;T;T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.21	N
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.;.;N;.;.;N;N
MutationTaster	Benign	0.99	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;D;N;N;N
REVEL	Benign	0.044
Sift	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.091	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;D;D;D;D;D;D;D;.;.;.;D;.
Vest4		0.25
MutPred		0.20		.;.;.;.;.;.;.;.;Loss of catalytic residue at P24 (P = 0.0175);Loss of catalytic residue at P24 (P = 0.0175);Loss of catalytic residue at P24 (P = 0.0175);Loss of catalytic residue at P24 (P = 0.0175);Loss of catalytic residue at P24 (P = 0.0175);
MVP		0.43
MPC		0.72
ClinPred		0.78	D
GERP RS		2.5
Varity_R		0.11
gMVP		0.12

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: rs768901573; hg19: chr14-24837619;