rs777561014

Variant names:

• chr18-79396313-C-T
• rs777561014
• NM_001278669.2:c.89C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-79396313-C-T
• chr18-79396313-C-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001278669.2(NFATC1):​c.89C>T​(p.Ala30Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000038 in 1,421,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: NFATC1 NM_001278669.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.298
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022107631).
• BS2: High AC in GnomAdExome4 at 52 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278669.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFATC1	NM_001278669.2	MANE Select	c.89C>T	p.Ala30Val	missense	Exon 1 of 10	NP_001265598.1	O95644-1
	NFATC1	NM_006162.5		c.89C>T	p.Ala30Val	missense	Exon 1 of 10	NP_006153.2
	NFATC1	NM_172390.3		c.89C>T	p.Ala30Val	missense	Exon 1 of 8	NP_765978.1	O95644-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFATC1	ENST00000427363.7	TSL:1 MANE Select	c.89C>T	p.Ala30Val	missense	Exon 1 of 10	ENSP00000389377.2	O95644-1
	NFATC1	ENST00000253506.9	TSL:1	c.89C>T	p.Ala30Val	missense	Exon 1 of 10	ENSP00000253506.5	O95644-4
	NFATC1	ENST00000591814.5	TSL:1	c.89C>T	p.Ala30Val	missense	Exon 1 of 8	ENSP00000466194.1	O95644-2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151428 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000975 AC: 1 AN: 102522 AF XY: 0.0000173

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000280

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000409 AC: 52 AN: 1270302 Hom.: 0 Cov.: 32 AF XY: 0.0000495 AC XY: 31 AN XY: 626764

African (AFR) AF: 0.00 AC: 0 AN: 25802

American (AMR) AF: 0.00 AC: 0 AN: 26356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20936

East Asian (EAS) AF: 0.00191 AC: 50 AN: 26196

South Asian (SAS) AF: 0.00 AC: 0 AN: 66622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4538

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1005494

Other (OTH) AF: 0.0000399 AC: 2 AN: 50178

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151428 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73956

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41326

American (AMR) AF: 0.00 AC: 0 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67792

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000184 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.30
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.022
Sift	Benign	0.041	D
Sift4G	Benign	0.085	T
Polyphen		0.22	B
Vest4		0.060
MutPred		0.16		Loss of methylation at R32 (P = 0.068)
MVP		0.14
ClinPred		0.081	T
GERP RS		-0.24
PromoterAI		-0.0090	Neutral
Varity_R		0.079
gMVP		0.17
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs777561014; hg19: chr18-77156313;