18-79396328-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001278669.2(NFATC1):c.104G>A(p.Gly35Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000993 in 1,405,140 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict 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 Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. G35G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (6 hom.)
• Consequence: NFATC1 NM_001278669.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.12

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002750963).
• BP6: Variant 18-79396328-G-A is Benign according to our data. Variant chr18-79396328-G-A is described in ClinVar as [Benign]. Clinvar id is 712224.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00528 (797/151082) while in subpopulation AFR AF= 0.0184 (758/41264). AF 95% confidence interval is 0.0173. There are 4 homozygotes in gnomad4. There are 381 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 785 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFATC1	NM_001278669.2	c.104G>A	p.Gly35Asp	missense_variant	1/10	ENST00000427363.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFATC1	ENST00000427363.7	c.104G>A	p.Gly35Asp	missense_variant	1/10	1	NM_001278669.2	P4

Frequencies

GnomAD3 genomes AF: 0.00520 AC: 785 AN: 150976 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00624

GnomAD3 exomes AF: 0.000693 AC: 67 AN: 96634 Hom.: 0 AF XY: 0.000460 AC XY: 25 AN XY: 54326

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.000900

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000580

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000411

GnomAD4 exome AF: 0.000477 AC: 598 AN: 1254058 Hom.: 6 Cov.: 32 AF XY: 0.000409 AC XY: 253 AN XY: 617976

Gnomad4 AFR exome AF: 0.0191

Gnomad4 AMR exome AF: 0.00135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000502

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00528 AC: 797 AN: 151082 Hom.: 4 Cov.: 32 AF XY: 0.00516 AC XY: 381 AN XY: 73884

Gnomad4 AFR AF: 0.0184

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00618

Alfa AF: 0.000570 Hom.: 0

Bravo AF: 0.00634

ESP6500AA AF: 0.0141 AC: 58

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000964 AC: 100

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.50	T;T;T;T;T
MetaRNN	Benign	0.0028	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.69	N;N;.;N;N
MutationTaster	Benign	1.0	D;N;N;N;N;N
PROVEAN	Benign	-0.090	N;.;.;N;.
REVEL	Benign	0.022
Sift	Uncertain	0.010	D;.;.;D;.
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.27	.;.;.;.;B
Vest4		0.084
MVP		0.17
ClinPred		0.011	T
GERP RS		1.3
Varity_R		0.12
gMVP		0.16

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: rs200585424; hg19: chr18-77156328; COSMIC: COSV53708361; COSMIC: COSV53708361;