rs56368098

Positions:

• chr16-69691794-T-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_138713.4(NFAT5):​c.1969T>G​(p.Ser657Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,614,096 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (12 hom.)
• Consequence: NFAT5 NM_138713.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.34

Genes affected

NFAT5 (HGNC:7774): (nuclear factor of activated T cells 5) The product of this gene is a member of the nuclear factors of activated T cells family of transcription factors. Proteins belonging to this family play a central role in inducible gene transcription during the immune response. This protein regulates gene expression induced by osmotic stress in mammalian cells. Unlike monomeric members of this protein family, this protein exists as a homodimer and forms stable dimers with DNA elements. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NFAT5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0050411224).
• BP6: Variant 16-69691794-T-G is Benign according to our data. Variant chr16-69691794-T-G is described in ClinVar as [Benign]. Clinvar id is 526786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-69691794-T-G is described in Lovd as [Likely_benign]. Variant chr16-69691794-T-G is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 246 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFAT5	NM_138713.4	c.1969T>G	p.Ser657Ala	missense_variant	13/15	ENST00000349945.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFAT5	ENST00000349945.7	c.1969T>G	p.Ser657Ala	missense_variant	13/15	1	NM_138713.4	A2

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 246 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00228 AC: 572 AN: 251330 Hom.: 2 AF XY: 0.00238 AC XY: 323 AN XY: 135844

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00863

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00324

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00259

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00238 AC: 3483 AN: 1461864 Hom.: 12 Cov.: 32 AF XY: 0.00242 AC XY: 1763 AN XY: 727230

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00861

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00347

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.00238

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.00162 AC: 246 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74446

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00262 Hom.: 2

Bravo AF: 0.00192

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00226 AC: 274

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00290

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NFAT5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Immunodeficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T;T;T;T;.;.
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.0050	T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.78	N;N;N;.;N;N
REVEL	Benign	0.069
Sift	Uncertain	0.0040	D;D;D;.;D;D
Sift4G	Benign	0.22	T;T;T;T;T;T
Polyphen		0.18	.;B;.;.;.;.
Vest4		0.29
MVP		0.60
ClinPred		0.034	T
GERP RS		6.1
Varity_R		0.11

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: rs56368098; hg19: chr16-69725697;