Genetic Variant NM_001278669.2:c.140A>T (chr18-79410415-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001278669.2(NFATC1):c.140A>T(p.Tyr47Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,620 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NFATC1
NM_001278669.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.23

Variant links:

Genes affected

NFATC1 (HGNC:7775): (nuclear factor of activated T cells 1) The product of this gene is a component of the nuclear factor 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. Proteins belonging to this family of transcription factors play a central role in inducible gene transcription during immune response. The product of this gene is an inducible nuclear component. It functions as a major molecular target for the immunosuppressive drugs such as cyclosporin A. Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. Different isoforms of this protein may regulate inducible expression of different cytokine genes. [provided by RefSeq, Jul 2013]

NFATC1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3044167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFATC1	NM_001278669.2 link	c.140A>T	p.Tyr47Phe	missense_variant	Exon 2 of 10	ENST00000427363.7	NP_001265598.1	O95644-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFATC1	ENST00000427363.7 link	c.140A>T	p.Tyr47Phe	missense_variant	Exon 2 of 10	1	NM_001278669.2	ENSP00000389377.2		O95644-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000408

AC:

AN:

245088

Hom.:

AF XY:

0.00

AC XY:

AN XY:

132746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457620

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725126

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.013

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

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

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

M_CAP

Benign

0.015

MetaRNN

Benign

0.30

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

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.9

L;L;.;L;L;.;.;.;.

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.79

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

REVEL

Benign

0.21

Sift

Benign

0.057

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

Sift4G

Benign

0.38

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

Polyphen

0.99

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

Vest4

0.46

MutPred

0.41

Loss of phosphorylation at Y47 (P = 0.0065);Loss of phosphorylation at Y47 (P = 0.0065);Loss of phosphorylation at Y47 (P = 0.0065);Loss of phosphorylation at Y47 (P = 0.0065);Loss of phosphorylation at Y47 (P = 0.0065);.;.;.;.;

MVP

0.63

MPC

0.22

ClinPred

0.18

GERP RS

2.0

Varity_R

0.064

gMVP

0.26

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over