Genetic Variant NFATC1:p.Val210Leu (chr18-79410903-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001278669.2(NFATC1):c.628G>C(p.Val210Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,166 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V210M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NFATC1
NM_001278669.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.64

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

congenital heart disease
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

NFATC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFATC1	NM_001278669.2 link	c.628G>C	p.Val210Leu	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.628G>C	p.Val210Leu	missense_variant	Exon 2 of 10	1	NM_001278669.2	ENSP00000389377.2		O95644-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1456166

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724268

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44550

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25904

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

85866

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49968

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110760

Other (OTH)

AF:

0.00

AC:

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

.;.;T;.;D;.;.;.;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

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

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.63

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

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.5

M;M;.;M;M;.;.;.;.

PhyloP100

9.6

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.9

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

REVEL

Benign

0.24

Sift

Uncertain

0.0060

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

Sift4G

Benign

0.25

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

Polyphen

1.0

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

Vest4

0.74

MutPred

0.23

Loss of glycosylation at S211 (P = 0.0897);Loss of glycosylation at S211 (P = 0.0897);Loss of glycosylation at S211 (P = 0.0897);Loss of glycosylation at S211 (P = 0.0897);Loss of glycosylation at S211 (P = 0.0897);.;.;.;.;

MVP

0.46

MPC

0.85

ClinPred

0.97

GERP RS

4.9

Varity_R

0.41

gMVP

0.45

Mutation Taster

=6/94

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over