Variant 14-24368417-T-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.77T>G(p.Leu26Arg) 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. 13/21 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. L26P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NFATC4
NM_004554.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.76

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 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=0.22246754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFATC4	NM_004554.5 linkuse as main transcript	c.77T>G	p.Leu26Arg	missense_variant	1/10	ENST00000250373.9
LOC124903291	XR_007064085.1 linkuse as main transcript	n.139+830A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFATC4	ENST00000250373.9 linkuse as main transcript	c.77T>G	p.Leu26Arg	missense_variant	1/10	1	NM_004554.5	P1	Q14934-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000340

AC:

AN:

1176928

Hom.:

Cov.:

AF XY:

0.00000177

AC XY:

AN XY:

565394

show subpopulations

Gnomad4 AFR exome

AF:

0.0000421

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000367

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000207

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Jul 06, 2021

The c.77T>G (p.L26R) alteration is located in exon 1 (coding exon 1) of the NFATC4 gene. This alteration results from a T to G substitution at nucleotide position 77, causing the leucine (L) at amino acid position 26 to be replaced by an arginine (R). 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

0.071

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.017

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

Eigen

Benign

0.14

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.68

M_CAP

Benign

0.041

MetaRNN

Benign

0.22

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

0.96

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

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.41

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

REVEL

Benign

0.11

Sift

Benign

0.040

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

Sift4G

Benign

0.59

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

0.48

MutPred

0.15

.;.;.;.;.;.;.;.;Gain of methylation at L26 (P = 0.034);Gain of methylation at L26 (P = 0.034);Gain of methylation at L26 (P = 0.034);Gain of methylation at L26 (P = 0.034);Gain of methylation at L26 (P = 0.034);

MVP

0.17

MPC

1.1

ClinPred

0.74

GERP RS

3.5

Varity_R

0.30

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over