16-68122295-C-T

Variant summary

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

The NM_173165.3(NFATC3):c.412C>T(p.Arg138Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,614,064 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (19 hom.)
• Consequence: NFATC3 NM_173165.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.62

Genes affected

NFATC3 (HGNC:7777): (nuclear factor of activated T cells 3) The product of this gene is a member of the nuclear factors 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. Other members of this family participate to form this complex also. The product of this gene plays a role in the regulation of gene expression in T cells and immature thymocytes. Several transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033489466).
• BP6: Variant 16-68122295-C-T is Benign according to our data. Variant chr16-68122295-C-T is described in ClinVar as [Benign]. Clinvar id is 788366.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1618/152194) while in subpopulation AFR AF= 0.0372 (1546/41518). AF 95% confidence interval is 0.0357. There are 34 homozygotes in gnomad4. There are 774 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 1615 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFATC3	NM_173165.3	c.412C>T	p.Arg138Trp	missense_variant	2/10	ENST00000346183.8
NFATC3	NM_004555.4	c.412C>T	p.Arg138Trp	missense_variant	2/11
NFATC3	NM_173163.3	c.412C>T	p.Arg138Trp	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFATC3	ENST00000346183.8	c.412C>T	p.Arg138Trp	missense_variant	2/10	1	NM_173165.3	P3

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1615 AN: 152076 Hom.: 34 Cov.: 31

Gnomad AFR AF: 0.0373

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00272 AC: 684 AN: 251088 Hom.: 8 AF XY: 0.00200 AC XY: 272 AN XY: 135792

Gnomad AFR exome AF: 0.0387

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.00108 AC: 1577 AN: 1461870 Hom.: 19 Cov.: 35 AF XY: 0.000935 AC XY: 680 AN XY: 727232

Gnomad4 AFR exome AF: 0.0378

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000962

Gnomad4 OTH exome AF: 0.00217

GnomAD4 genome AF: 0.0106 AC: 1618 AN: 152194 Hom.: 34 Cov.: 31 AF XY: 0.0104 AC XY: 774 AN XY: 74410

Gnomad4 AFR AF: 0.0372

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00203 Hom.: 9

Bravo AF: 0.0121

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0355 AC: 156

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00345 AC: 419

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

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

Jan 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.046
Eigen_PC	Benign	-0.027
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.95	D;D;D;D
MetaRNN	Benign	0.0033	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.90	D;D;D;D
PrimateAI	Benign	0.36	T
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		0.99, 0.99	.;D;D;.
Vest4		0.30
MVP		0.15
MPC		0.20
ClinPred		0.027	T
GERP RS		3.0
Varity_R		0.053
gMVP		0.26

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: rs62636652; hg19: chr16-68156198;