chr16-69692980-A-G

Variant names:

• chr16-69692980-A-G
• rs1555534626
• NM_138713.4:c.3155A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_138713.4(NFAT5):​c.3155A>G​(p.Gln1052Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFAT5 NM_138713.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.15
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFAT5	NM_138713.4	c.3155A>G	p.Gln1052Arg	missense_variant	Exon 13 of 15	ENST00000349945.7	NP_619727.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFAT5	ENST00000349945.7	c.3155A>G	p.Gln1052Arg	missense_variant	Exon 13 of 15	1	NM_138713.4	ENSP00000338806.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency Uncertain:1

Sep 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 526777). This variant has not been reported in the literature in individuals affected with NFAT5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 958 of the NFAT5 protein (p.Gln958Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	.;T;.;.;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D;D;D;.;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.32	T;T;T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.9	.;L;.;.;.;.
PhyloP100		5.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N;N;N;.;N;N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D;D;D;.;D;D
Sift4G	Uncertain	0.031	D;D;D;D;D;D
Polyphen		0.99	.;D;.;.;.;.
Vest4		0.48
MutPred		0.24		.;Gain of MoRF binding (P = 0.0197);.;.;.;.;
MVP		0.65
ClinPred		0.90	D
GERP RS		6.0
Varity_R		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 23

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555534626; hg19: chr16-69726883;