Variant 14-24368413-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004554.5(NFATC4):c.73C>A(p.Pro25Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 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 (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000067 ( 0 hom. )

Consequence

NFATC4
NM_004554.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.68

Variant links:

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]

NFATC4 links:

LOC124903291 (HGNC:):

LOC124903291 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02743861).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFATC4	NM_004554.5 link	c.73C>A	p.Pro25Thr	missense_variant	1/10	ENST00000250373.9	NP_004545.2	Q14934-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFATC4	ENST00000250373.9 link	c.73C>A	p.Pro25Thr	missense_variant	1/10	1	NM_004554.5	ENSP00000250373.4		Q14934-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151906

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000390

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000567

AC:

AN:

35260

Hom.:

AF XY:

0.0000561

AC XY:

AN XY:

17826

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000972

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000669

AC:

AN:

1196126

Hom.:

Cov.:

AF XY:

0.00000522

AC XY:

AN XY:

574946

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000714

Gnomad4 SAS exome

AF:

0.000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000207

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151906

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74172

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000390

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000275

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2024

The c.73C>A (p.P25T) alteration is located in exon 1 (coding exon 1) of the NFATC4 gene. This alteration results from a C to A substitution at nucleotide position 73, causing the proline (P) at amino acid position 25 to be replaced by a threonine (T). 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

0.072

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.064

.;.;.;.;.;.;.;.;.;T;T;T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Benign

0.56

M_CAP

Benign

0.067

MetaRNN

Benign

0.027

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.;.;N;.;.;N;N

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.2

N;N;N;N;N;N;N;N;N;D;N;N;N

REVEL

Benign

0.050

Sift

Uncertain

0.0030

D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Benign

0.10

T;T;T;T;T;T;T;T;T;T;D;T;T

Polyphen

1.0

D;D;D;D;D;D;D;D;.;.;.;D;.

Vest4

0.30

MutPred

0.23

.;.;.;.;.;.;.;.;Loss of catalytic residue at P24 (P = 0.016);Loss of catalytic residue at P24 (P = 0.016);Loss of catalytic residue at P24 (P = 0.016);Loss of catalytic residue at P24 (P = 0.016);Loss of catalytic residue at P24 (P = 0.016);

MVP

0.44

MPC

0.88

ClinPred

0.33

GERP RS

2.5

Varity_R

0.19

gMVP

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over