chr18-79467476-A-G

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.1901A>G(p.His634Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,602,740 control chromosomes in the GnomAD database, including 89,656 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 0.40 ( 13320 hom., cov: 32)

Exomes 𝑓: 0.32 ( 76336 hom. )

Consequence

NFATC1
ENST00000587635.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.08

Publications

14 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=5.4692257E-5).

BP6

Variant 18-79467476-A-G is Benign according to our data. Variant chr18-79467476-A-G is described in ClinVar as Benign. ClinVar VariationId is 1668933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.602 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.1986A>G	p.Pro662Pro	synonymous	Exon 8 of 10	NP_001265598.1
NFATC1	NM_172387.3		c.1947A>G	p.Pro649Pro	synonymous	Exon 8 of 10	NP_765975.1
NFATC1	NM_006162.5		c.1986A>G	p.Pro662Pro	synonymous	Exon 8 of 10	NP_006153.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NFATC1	ENST00000587635.5	TSL:1	c.1901A>G	p.His634Arg	missense	Exon 8 of 8	ENSP00000468111.1
NFATC1	ENST00000427363.7	TSL:1 MANE Select	c.1986A>G	p.Pro662Pro	synonymous	Exon 8 of 10	ENSP00000389377.2
NFATC1	ENST00000329101.8	TSL:1	c.1947A>G	p.Pro649Pro	synonymous	Exon 8 of 10	ENSP00000327850.3

Frequencies

GnomAD3 genomes

AF:

0.396

AC:

60228

AN:

151900

Hom.:

13294

Cov.:

show subpopulations

Gnomad AFR

AF:

0.608

Gnomad AMI

AF:

0.352

Gnomad AMR

AF:

0.344

Gnomad ASJ

AF:

0.327

Gnomad EAS

AF:

0.372

Gnomad SAS

AF:

0.222

Gnomad FIN

AF:

0.322

Gnomad MID

AF:

0.291

Gnomad NFE

AF:

0.311

Gnomad OTH

AF:

0.367

GnomAD2 exomes

AF:

0.325

AC:

80474

AN:

247962

AF XY:

0.315

show subpopulations

Gnomad AFR exome

AF:

0.604

Gnomad AMR exome

AF:

0.326

Gnomad ASJ exome

AF:

0.318

Gnomad EAS exome

AF:

0.382

Gnomad FIN exome

AF:

0.308

Gnomad NFE exome

AF:

0.309

Gnomad OTH exome

AF:

0.306

GnomAD4 exome

AF:

0.319

AC:

462826

AN:

1450722

Hom.:

76336

Cov.:

AF XY:

0.315

AC XY:

227056

AN XY:

720626

show subpopulations

African (AFR)

AF:

0.619

AC:

19617

AN:

31680

American (AMR)

AF:

0.324

AC:

14302

AN:

44136

Ashkenazi Jewish (ASJ)

AF:

0.316

AC:

8139

AN:

25724

East Asian (EAS)

AF:

0.386

AC:

15162

AN:

39306

South Asian (SAS)

AF:

0.220

AC:

18822

AN:

85376

European-Finnish (FIN)

AF:

0.316

AC:

16804

AN:

53252

Middle Eastern (MID)

AF:

0.299

AC:

1709

AN:

5712

European-Non Finnish (NFE)

AF:

0.315

AC:

348509

AN:

1105628

Other (OTH)

AF:

0.330

AC:

19762

AN:

59908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

15110

30219

45329

60438

75548

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11596

23192

34788

46384

57980

<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:

0.397

AC:

60309

AN:

152018

Hom.:

13320

Cov.:

AF XY:

0.392

AC XY:

29141

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.608

AC:

25188

AN:

41440

American (AMR)

AF:

0.345

AC:

5262

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.327

AC:

1136

AN:

3472

East Asian (EAS)

AF:

0.372

AC:

1915

AN:

5150

South Asian (SAS)

AF:

0.223

AC:

1075

AN:

4824

European-Finnish (FIN)

AF:

0.322

AC:

3406

AN:

10586

Middle Eastern (MID)

AF:

0.286

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.311

AC:

21157

AN:

67960

Other (OTH)

AF:

0.362

AC:

766

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1758

3517

5275

7034

8792

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

542

1084

1626

2168

2710

<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:

0.352

Hom.:

23247

Bravo

AF:

0.412

TwinsUK

AF:

0.308

AC:

1142

ALSPAC

AF:

0.317

AC:

1220

ESP6500AA

AF:

0.606

AC:

2671

ESP6500EA

AF:

0.323

AC:

2780

ExAC

AF:

0.331

AC:

40147

Asia WGS

AF:

0.301

AC:

1046

AN:

3476

EpiCase

AF:

0.307

EpiControl

AF:

0.311

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NFATC1-related disorder

Benign:1

Oct 22, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.022

(source)

DANN

Benign

0.25

DEOGEN2

Benign

0.014

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.18

MetaRNN

Benign

0.000055

PhyloP100

-4.1

Vest4

0.038

GERP RS

-9.4

Mutation Taster

=96/4

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over