Variant 14-24369837-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004554.5(NFATC4):c.439C>G(p.Pro147Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,410 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NFATC4
NM_004554.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.08

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:

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ACMG classification

Classification made for transcript

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=0.13921231).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFATC4	NM_004554.5 linkuse as main transcript	c.439C>G	p.Pro147Ala	missense_variant	2/10	ENST00000250373.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFATC4	ENST00000250373.9 linkuse as main transcript	c.439C>G	p.Pro147Ala	missense_variant	2/10	1	NM_004554.5	P1	Q14934-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000443

AC:

AN:

225550

Hom.:

AF XY:

0.00000805

AC XY:

AN XY:

124268

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000589

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:

0.00000138

AC:

AN:

1453410

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722552

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000507

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

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

Apr 15, 2024

The c.439C>G (p.P147A) alteration is located in exon 2 (coding exon 2) of the NFATC4 gene. This alteration results from a C to G substitution at nucleotide position 439, causing the proline (P) at amino acid position 147 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

0.058

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.25

DEOGEN2

Benign

0.13

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

Eigen

Benign

0.092

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.93

M_CAP

Benign

0.0076

MetaRNN

Benign

0.14

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

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

MutationTaster

Benign

0.53

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

PrimateAI

Uncertain

0.66

PROVEAN

Benign

0.79

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.044

Sift

Benign

0.17

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

Sift4G

Benign

0.39

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

Polyphen

0.94

P;P;P;P;P;P;P;P;.;P;.;.;.;.;.;P;.;P;P

Vest4

0.21

MutPred

0.41

.;.;.;.;.;.;.;.;Loss of catalytic residue at P147 (P = 0.0271);Loss of catalytic residue at P147 (P = 0.0271);Loss of catalytic residue at P147 (P = 0.0271);.;.;.;.;.;.;.;.;

MVP

0.20

MPC

0.49

ClinPred

0.12

GERP RS

3.6

Varity_R

0.041

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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