rs148886916

Variant names:

• chr16-69647204-A-G
• rs148886916
• NM_138713.4:c.430A>G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_138713.4(NFAT5):​c.430A>G​(p.Ser144Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,614,116 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.00047 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: NFAT5 NM_138713.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.63

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011232048).
• BP6: Variant 16-69647204-A-G is Benign according to our data. Variant chr16-69647204-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 456654.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 71 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFAT5	NM_138713.4	c.430A>G	p.Ser144Gly	missense_variant	Exon 4 of 15	ENST00000349945.7	NP_619727.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFAT5	ENST00000349945.7	c.430A>G	p.Ser144Gly	missense_variant	Exon 4 of 15	1	NM_138713.4	ENSP00000338806.3

Frequencies

GnomAD3 genomes AF: 0.000466 AC: 71 AN: 152214 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000493 AC: 124 AN: 251284 Hom.: 0 AF XY: 0.000508 AC XY: 69 AN XY: 135798

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000598

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000477 AC: 697 AN: 1461784 Hom.: 0 Cov.: 31 AF XY: 0.000473 AC XY: 344 AN XY: 727176

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000489

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.000466 AC: 71 AN: 152332 Hom.: 1 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74488

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000560 Hom.: 0

Bravo AF: 0.000529

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000371 AC: 45

EpiCase AF: 0.000763

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Dec 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.430A>G (p.S144G) alteration is located in exon 4 (coding exon 4) of the NFAT5 gene. This alteration results from a A to G substitution at nucleotide position 430, causing the serine (S) at amino acid position 144 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Immunodeficiency Benign:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	22
DANN	Benign	0.77
DEOGEN2	Benign	0.25	.;T;.;.;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.66	T;T;T;T;.;.
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.011	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.080	.;N;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.58	N;N;N;.;N;N
REVEL	Benign	0.081
Sift	Benign	0.44	T;T;T;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	.;B;.;.;.;.
Vest4		0.094
MVP		0.23
ClinPred		0.0034	T
GERP RS		2.1
Varity_R		0.028

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148886916; hg19: chr16-69681107; COSMIC: COSV63028146;