18-79400385-A-ACCCGC

Variant names:

• chr18-79400385-A-ACCCGC
• rs749645871
• ENST00000329101.8:c.-5_-1dupCCGCC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_172387.3(NFATC1):​c.-5_-1dupCCGCC​(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,044,608 control chromosomes in the GnomAD database, including 30 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.010 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (13 hom.)
• Consequence: NFATC1 NM_172387.3 frameshift, start_lost
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.11
• 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 -9 ACMG points.

• BP6: Variant 18-79400385-A-ACCCGC is Benign according to our data. Variant chr18-79400385-A-ACCCGC is described in ClinVar as Benign. ClinVar VariationId is 3053678.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (1215/120136) while in subpopulation AFR AF = 0.0328 (1074/32792). AF 95% confidence interval is 0.0311. There are 17 homozygotes in GnomAd4. There are 580 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1215 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172387.3. 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.127+4036_127+4040dupCCGCC		intron	N/A	NP_001265598.1	O95644-1
	NFATC1	NM_172387.3		c.-5_-1dupCCGCC	p.Met1fs	frameshift start_lost	Exon 1 of 10	NP_765975.1	O95644-6
	NFATC1	NM_172389.3		c.-5_-1dupCCGCC	p.Met1fs	frameshift start_lost	Exon 1 of 10	NP_765977.1	O95644-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFATC1	ENST00000329101.8	TSL:1	c.-5_-1dupCCGCC	p.Met1fs	frameshift start_lost	Exon 1 of 10	ENSP00000327850.3	O95644-6
	NFATC1	ENST00000318065.9	TSL:1	c.-5_-1dupCCGCC	p.Met1fs	frameshift start_lost	Exon 1 of 10	ENSP00000316553.5	O95644-5
	NFATC1	ENST00000592223.5	TSL:1	c.-5_-1dupCCGCC	p.Met1fs	frameshift start_lost	Exon 1 of 8	ENSP00000467181.1	O95644-3

Frequencies

GnomAD3 genomes AF: 0.00994 AC: 1193 AN: 120028 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000281

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00490

Gnomad NFE AF: 0.000466

Gnomad OTH AF: 0.00730

GnomAD2 exomes AF: 0.00190 AC: 124 AN: 65168 AF XY: 0.00199

Gnomad AFR exome AF: 0.0389

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00374

GnomAD4 exome AF: 0.00162 AC: 1500 AN: 924472 Hom.: 13 Cov.: 31 AF XY: 0.00152 AC XY: 710 AN XY: 466544

African (AFR) AF: 0.0393 AC: 770 AN: 19596

American (AMR) AF: 0.00290 AC: 68 AN: 23480

Ashkenazi Jewish (ASJ) AF: 0.0102 AC: 189 AN: 18492

East Asian (EAS) AF: 0.00 AC: 0 AN: 25556

South Asian (SAS) AF: 0.000113 AC: 7 AN: 61878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41666

Middle Eastern (MID) AF: 0.0121 AC: 45 AN: 3716

European-Non Finnish (NFE) AF: 0.000268 AC: 185 AN: 689668

Other (OTH) AF: 0.00584 AC: 236 AN: 40420

GnomAD4 genome AF: 0.0101 AC: 1215 AN: 120136 Hom.: 17 Cov.: 32 AF XY: 0.00988 AC XY: 580 AN XY: 58678

African (AFR) AF: 0.0328 AC: 1074 AN: 32792

American (AMR) AF: 0.00595 AC: 74 AN: 12430

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 28 AN: 2700

East Asian (EAS) AF: 0.00 AC: 0 AN: 3764

South Asian (SAS) AF: 0.000280 AC: 1 AN: 3568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8614

Middle Eastern (MID) AF: 0.00510 AC: 1 AN: 196

European-Non Finnish (NFE) AF: 0.000466 AC: 25 AN: 53630

Other (OTH) AF: 0.00722 AC: 12 AN: 1662

Alfa AF: 0.00725 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	NFATC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=300/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs749645871; hg19: chr18-77160385;