18-79486406-T-G

Position:

• chr18-79486406-T-G

Variant summary

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

The NM_001278669.2(NFATC1):​c.2251T>G​(p.Cys751Gly) variant causes a missense change. The variant allele was found at a frequency of 0.438 in 1,612,454 control chromosomes in the GnomAD database, including 158,302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.38 (12087 hom., cov: 33)
  • Exomes 𝑓: 0.44 (146215 hom.)
• Consequence: NFATC1 NM_001278669.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.90

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=0.0010785162).
• BP6: Variant 18-79486406-T-G is Benign according to our data. Variant chr18-79486406-T-G is described in ClinVar as [Benign]. Clinvar id is 1640667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-79486406-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFATC1	NM_001278669.2	c.2251T>G	p.Cys751Gly	missense_variant	9/10	ENST00000427363.7	NP_001265598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFATC1	ENST00000427363.7	c.2251T>G	p.Cys751Gly	missense_variant	9/10	1	NM_001278669.2	ENSP00000389377.2

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57478 AN: 151872 Hom.: 12095 Cov.: 33

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.431

GnomAD3 exomes AF: 0.424 AC: 106033 AN: 250046 Hom.: 23432 AF XY: 0.432 AC XY: 58459 AN XY: 135414

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.403

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.345

Gnomad SAS exome AF: 0.395

Gnomad FIN exome AF: 0.484

Gnomad NFE exome AF: 0.467

Gnomad OTH exome AF: 0.465

GnomAD4 exome AF: 0.444 AC: 647999 AN: 1460464 Hom.: 146215 Cov.: 76 AF XY: 0.445 AC XY: 323042 AN XY: 726536

Gnomad4 AFR exome AF: 0.181

Gnomad4 AMR exome AF: 0.407

Gnomad4 ASJ exome AF: 0.497

Gnomad4 EAS exome AF: 0.376

Gnomad4 SAS exome AF: 0.397

Gnomad4 FIN exome AF: 0.476

Gnomad4 NFE exome AF: 0.456

Gnomad4 OTH exome AF: 0.433

GnomAD4 genome AF: 0.378 AC: 57472 AN: 151990 Hom.: 12087 Cov.: 33 AF XY: 0.383 AC XY: 28420 AN XY: 74274

Gnomad4 AFR AF: 0.182

Gnomad4 AMR AF: 0.443

Gnomad4 ASJ AF: 0.489

Gnomad4 EAS AF: 0.356

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.475

Gnomad4 NFE AF: 0.462

Gnomad4 OTH AF: 0.429

Alfa AF: 0.454 Hom.: 20781

Bravo AF: 0.369

TwinsUK AF: 0.463 AC: 1715

ALSPAC AF: 0.456 AC: 1758

ESP6500AA AF: 0.183 AC: 808

ESP6500EA AF: 0.463 AC: 3984

ExAC AF: 0.415 AC: 50385

Asia WGS AF: 0.340 AC: 1184 AN: 3478

EpiCase AF: 0.479

EpiControl AF: 0.487

ClinVar

Significance: Benign

Submissions summary: Benign:2

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	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.69
DEOGEN2	Pathogenic	0.80	.;.;D;.;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.47	T;T;T;T;T;T
MetaRNN	Benign	0.0011	T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.8	M;.;M;.;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.1	D;D;.;D;.;D
REVEL	Benign	0.10
Sift	Uncertain	0.010	D;D;.;D;.;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D
Polyphen		0.87	.;.;P;.;.;.
Vest4		0.35
MPC		0.47
ClinPred		0.067	T
GERP RS		3.5
Varity_R		0.72
gMVP		0.42

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: rs754093; hg19: chr18-77246406; COSMIC: COSV53701053;