ENST00000587635.5:c.1766T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000587635.5(NFATC1):c.1766T>C(p.Leu589Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,612,000 control chromosomes in the GnomAD database, including 26,788 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 5459 hom., cov: 33)

Exomes 𝑓: 0.16 ( 21329 hom. )

Consequence

NFATC1
ENST00000587635.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.62

Publications

13 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.5486946E-4).

BP6

Variant 18-79451764-T-C is Benign according to our data. Variant chr18-79451764-T-C is described in ClinVar as Benign. ClinVar VariationId is 1664128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000587635.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NFATC1	NM_001278669.2	MANE Select	c.1851T>C	p.Ser617Ser	synonymous	Exon 6 of 10	NP_001265598.1
NFATC1	NM_172387.3		c.1812T>C	p.Ser604Ser	synonymous	Exon 6 of 10	NP_765975.1
NFATC1	NM_006162.5		c.1851T>C	p.Ser617Ser	synonymous	Exon 6 of 10	NP_006153.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NFATC1	ENST00000587635.5	TSL:1	c.1766T>C	p.Leu589Pro	missense	Exon 6 of 8	ENSP00000468111.1
NFATC1	ENST00000427363.7	TSL:1 MANE Select	c.1851T>C	p.Ser617Ser	synonymous	Exon 6 of 10	ENSP00000389377.2
NFATC1	ENST00000329101.8	TSL:1	c.1812T>C	p.Ser604Ser	synonymous	Exon 6 of 10	ENSP00000327850.3

Frequencies

GnomAD3 genomes

AF:

0.234

AC:

35593

AN:

152042

Hom.:

5451

Cov.:

show subpopulations

Gnomad AFR

AF:

0.417

Gnomad AMI

AF:

0.278

Gnomad AMR

AF:

0.171

Gnomad ASJ

AF:

0.291

Gnomad EAS

AF:

0.383

Gnomad SAS

AF:

0.197

Gnomad FIN

AF:

0.111

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.144

Gnomad OTH

AF:

0.237

GnomAD2 exomes

AF:

0.186

AC:

46492

AN:

249772

AF XY:

0.184

show subpopulations

Gnomad AFR exome

AF:

0.414

Gnomad AMR exome

AF:

0.139

Gnomad ASJ exome

AF:

0.297

Gnomad EAS exome

AF:

0.383

Gnomad FIN exome

AF:

0.106

Gnomad NFE exome

AF:

0.142

Gnomad OTH exome

AF:

0.176

GnomAD4 exome

AF:

0.156

AC:

228012

AN:

1459840

Hom.:

21329

Cov.:

AF XY:

0.157

AC XY:

114075

AN XY:

726120

show subpopulations

African (AFR)

AF:

0.425

AC:

14188

AN:

33348

American (AMR)

AF:

0.142

AC:

6311

AN:

44552

Ashkenazi Jewish (ASJ)

AF:

0.296

AC:

7704

AN:

26064

East Asian (EAS)

AF:

0.394

AC:

15562

AN:

39536

South Asian (SAS)

AF:

0.189

AC:

16258

AN:

85798

European-Finnish (FIN)

AF:

0.108

AC:

5735

AN:

53300

Middle Eastern (MID)

AF:

0.288

AC:

1653

AN:

5748

European-Non Finnish (NFE)

AF:

0.134

AC:

149288

AN:

1111180

Other (OTH)

AF:

0.188

AC:

11313

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

9767

19535

29302

39070

48837

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5642

11284

16926

22568

28210

<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

AF:

0.234

AC:

35643

AN:

152160

Hom.:

5459

Cov.:

AF XY:

0.233

AC XY:

17322

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.417

AC:

17311

AN:

41482

American (AMR)

AF:

0.171

AC:

2611

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.291

AC:

1010

AN:

3472

East Asian (EAS)

AF:

0.383

AC:

1970

AN:

5148

South Asian (SAS)

AF:

0.198

AC:

955

AN:

4822

European-Finnish (FIN)

AF:

0.111

AC:

1181

AN:

10618

Middle Eastern (MID)

AF:

0.286

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.144

AC:

9774

AN:

68010

Other (OTH)

AF:

0.234

AC:

495

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1356

2711

4067

5422

6778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

354

708

1062

1416

1770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.171

Hom.:

6145

Bravo

AF:

0.249

TwinsUK

AF:

0.127

AC:

472

ALSPAC

AF:

0.134

AC:

515

ESP6500AA

AF:

0.406

AC:

1791

ESP6500EA

AF:

0.155

AC:

1334

ExAC

AF:

0.191

AC:

23227

Asia WGS

AF:

0.274

AC:

954

AN:

3478

EpiCase

AF:

0.153

EpiControl

AF:

0.163

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

NFATC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.049

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.075

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.16

MetaRNN

Benign

0.00025

PhyloP100

-2.6

Sift4G

Benign

0.29

Vest4

0.15

GERP RS

-4.1

Mutation Taster

=87/13

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over