rs754574529

Variant names:

• chr16-69693047-A-C
• rs754574529
• NM_138713.4:c.3222A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-69693047-A-C
• chr16-69693047-A-G

Variant summary

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

The NM_138713.4(NFAT5):​c.3222A>C​(p.Gln1074His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1074R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NFAT5 NM_138713.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.137
• 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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFAT5	NM_138713.4	MANE Select	c.3222A>C	p.Gln1074His	missense	Exon 13 of 15	NP_619727.2
	NFAT5	NM_001113178.3		c.3219A>C	p.Gln1073His	missense	Exon 13 of 15	NP_001106649.1
	NFAT5	NM_006599.4		c.3168A>C	p.Gln1056His	missense	Exon 12 of 14	NP_006590.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFAT5	ENST00000349945.7	TSL:1 MANE Select	c.3222A>C	p.Gln1074His	missense	Exon 13 of 15	ENSP00000338806.3
	NFAT5	ENST00000567239.5	TSL:1	c.3219A>C	p.Gln1073His	missense	Exon 13 of 15	ENSP00000457593.1
	NFAT5	ENST00000354436.6	TSL:1	c.3168A>C	p.Gln1056His	missense	Exon 12 of 14	ENSP00000346420.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461744 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727166

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.14
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.24		Gain of catalytic residue at Q1056 (P = 0.0867)
MVP		0.72
ClinPred		0.94	D
GERP RS		-7.9
Varity_R		0.49

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

Other links and lift over

dbSNP: rs754574529; hg19: chr16-69726950;