chr18-79467476-A-G

Position:

• chr18-79467476-A-G

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.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. 8/11 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.08

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 1668933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-79467476-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFATC1	NM_001278669.2	c.1986A>G	p.Pro662Pro	synonymous_variant	8/10	ENST00000427363.7	NP_001265598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFATC1	ENST00000427363.7	c.1986A>G	p.Pro662Pro	synonymous_variant	8/10	1	NM_001278669.2	ENSP00000389377.2

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60228 AN: 151900 Hom.: 13294 Cov.: 32

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

GnomAD3 exomes AF: 0.325 AC: 80474 AN: 247962 Hom.: 14025 AF XY: 0.315 AC XY: 42237 AN XY: 134254

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 SAS exome AF: 0.218

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.: 36 AF XY: 0.315 AC XY: 227056 AN XY: 720626

Gnomad4 AFR exome AF: 0.619

Gnomad4 AMR exome AF: 0.324

Gnomad4 ASJ exome AF: 0.316

Gnomad4 EAS exome AF: 0.386

Gnomad4 SAS exome AF: 0.220

Gnomad4 FIN exome AF: 0.316

Gnomad4 NFE exome AF: 0.315

Gnomad4 OTH exome AF: 0.330

GnomAD4 genome AF: 0.397 AC: 60309 AN: 152018 Hom.: 13320 Cov.: 32 AF XY: 0.392 AC XY: 29141 AN XY: 74300

Gnomad4 AFR AF: 0.608

Gnomad4 AMR AF: 0.345

Gnomad4 ASJ AF: 0.327

Gnomad4 EAS AF: 0.372

Gnomad4 SAS AF: 0.223

Gnomad4 FIN AF: 0.322

Gnomad4 NFE AF: 0.311

Gnomad4 OTH AF: 0.362

Alfa AF: 0.330 Hom.: 11601

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

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

Oct 22, 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	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.022
DANN	Benign	0.25
DEOGEN2	Benign	0.014	T
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.000055	T
Vest4		0.038
GERP RS		-9.4

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: rs25656; hg19: chr18-77227476; COSMIC: COSV53698423; COSMIC: COSV53698423;