rs15350

Positions:

• chr18-79451764-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 8/11 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.62

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 1664128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-79451764-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFATC1	NM_001278669.2	c.1851T>C	p.Ser617Ser	synonymous_variant	6/10	ENST00000427363.7	NP_001265598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFATC1	ENST00000427363.7	c.1851T>C	p.Ser617Ser	synonymous_variant	6/10	1	NM_001278669.2	ENSP00000389377.2

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35593 AN: 152042 Hom.: 5451 Cov.: 33

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

GnomAD3 exomes AF: 0.186 AC: 46492 AN: 249772 Hom.: 5592 AF XY: 0.184 AC XY: 24780 AN XY: 135026

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 SAS exome AF: 0.187

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.: 32 AF XY: 0.157 AC XY: 114075 AN XY: 726120

Gnomad4 AFR exome AF: 0.425

Gnomad4 AMR exome AF: 0.142

Gnomad4 ASJ exome AF: 0.296

Gnomad4 EAS exome AF: 0.394

Gnomad4 SAS exome AF: 0.189

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.234 AC: 35643 AN: 152160 Hom.: 5459 Cov.: 33 AF XY: 0.233 AC XY: 17322 AN XY: 74380

Gnomad4 AFR AF: 0.417

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.291

Gnomad4 EAS AF: 0.383

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.144

Gnomad4 OTH AF: 0.234

Alfa AF: 0.168 Hom.: 2328

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

NFATC1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2019

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.049
DANN	Benign	0.61
DEOGEN2	Benign	0.075	T
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.00025	T
Sift4G	Benign	0.29	T
Vest4		0.15
GERP RS		-4.1

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

Other links and lift over

dbSNP: rs15350; hg19: chr18-77211764; COSMIC: COSV53700536; COSMIC: COSV53700536;