rs56368098

Variant names:

• chr16-69691794-T-G
• rs56368098
• NM_138713.4:c.1969T>G
• NFAT5 p.Ser657Ala

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (12 hom.)
• Consequence: NFAT5 NM_138713.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.34
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -9 ACMG points.

• 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 526786.
• BS2: High AC in GnomAd4 at 246 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138713.4. 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
	NFAT5	NM_138713.4	MANE Select	c.1969T>G	p.Ser657Ala	missense	Exon 13 of 15	NP_619727.2	O94916-5
	NFAT5	NM_001113178.3		c.1966T>G	p.Ser656Ala	missense	Exon 13 of 15	NP_001106649.1	O94916-4
	NFAT5	NM_006599.4		c.1915T>G	p.Ser639Ala	missense	Exon 12 of 14	NP_006590.1	O94916-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFAT5	ENST00000349945.7	TSL:1 MANE Select	c.1969T>G	p.Ser657Ala	missense	Exon 13 of 15	ENSP00000338806.3	O94916-5
	NFAT5	ENST00000567239.5	TSL:1	c.1966T>G	p.Ser656Ala	missense	Exon 13 of 15	ENSP00000457593.1	O94916-4
	NFAT5	ENST00000354436.6	TSL:1	c.1915T>G	p.Ser639Ala	missense	Exon 12 of 14	ENSP00000346420.2	O94916-1

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

GnomAD2 exomes AF: 0.00228 AC: 572 AN: 251330 AF XY: 0.00238

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 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

African (AFR) AF: 0.000448 AC: 15 AN: 33478

American (AMR) AF: 0.00139 AC: 62 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00861 AC: 225 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00347 AC: 299 AN: 86254

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53418

Middle Eastern (MID) AF: 0.00676 AC: 39 AN: 5768

European-Non Finnish (NFE) AF: 0.00238 AC: 2646 AN: 1112002

Other (OTH) AF: 0.00286 AC: 173 AN: 60396

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

African (AFR) AF: 0.000433 AC: 18 AN: 41526

American (AMR) AF: 0.00203 AC: 31 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4820

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00228 AC: 155 AN: 68026

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00237 Hom.: 3

Bravo AF: 0.00192

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00290

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	Immunodeficiency (1)
-	-	1	NFAT5-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.069
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.22	T
Varity_R		0.11
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs56368098;

hg19: chr16-69725697;