rs145602190

Positions:

• chr16-69693577-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_138713.4(NFAT5):​c.3752A>G​(p.Gln1251Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00506 in 1,614,176 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (29 hom.)
• Consequence: NFAT5 NM_138713.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.99

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]

NFAT5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011267871).
• BP6: Variant 16-69693577-A-G is Benign according to our data. Variant chr16-69693577-A-G is described in ClinVar as [Benign]. Clinvar id is 456659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-69693577-A-G is described in Lovd as [Likely_benign]. Variant chr16-69693577-A-G is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 543 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFAT5	NM_138713.4	c.3752A>G	p.Gln1251Arg	missense_variant	13/15	ENST00000349945.7	NP_619727.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFAT5	ENST00000349945.7	c.3752A>G	p.Gln1251Arg	missense_variant	13/15	1	NM_138713.4	ENSP00000338806.3

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 543 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00567

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00354 AC: 889 AN: 251318 Hom.: 2 AF XY: 0.00357 AC XY: 485 AN XY: 135818

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00612

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00521 AC: 7622 AN: 1461890 Hom.: 29 Cov.: 33 AF XY: 0.00509 AC XY: 3704 AN XY: 727248

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.00259

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.00352

Gnomad4 NFE exome AF: 0.00631

Gnomad4 OTH exome AF: 0.00382

GnomAD4 genome AF: 0.00357 AC: 543 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.00340 AC XY: 253 AN XY: 74470

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00406

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00567

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00483 Hom.: 2

Bravo AF: 0.00322

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00346 AC: 420

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00442

EpiControl AF: 0.00498

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NFAT5-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2020

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

NFAT5: BP4, BS1, BS2 -

Immunodeficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;D;.;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.86	D;D;D;D;.;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.011	T;T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.3	.;M;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.94	N;N;N;.;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D;D;D;.;D;D
Sift4G	Uncertain	0.056	T;T;T;T;T;T
Polyphen		0.97	.;D;.;.;.;.
Vest4		0.75
MVP		0.63
ClinPred		0.029	T
GERP RS		4.8
Varity_R		0.43

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: rs145602190; hg19: chr16-69727480;