16-69691004-A-T

Variant names:

• chr16-69691004-A-T
• rs140085549
• NM_138713.4:c.1839A>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_138713.4(NFAT5):​c.1839A>T​(p.Pro613Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P613P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NFAT5 NM_138713.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP7: Synonymous conserved (PhyloP=1.12 with no splicing effect.

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.1839A>T	p.Pro613Pro	synonymous	Exon 12 of 15	NP_619727.2	O94916-5
	NFAT5	NM_001113178.3		c.1836A>T	p.Pro612Pro	synonymous	Exon 12 of 15	NP_001106649.1	O94916-4
	NFAT5	NM_006599.4		c.1785A>T	p.Pro595Pro	synonymous	Exon 11 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.1839A>T	p.Pro613Pro	synonymous	Exon 12 of 15	ENSP00000338806.3	O94916-5
	NFAT5	ENST00000567239.5	TSL:1	c.1836A>T	p.Pro612Pro	synonymous	Exon 12 of 15	ENSP00000457593.1	O94916-4
	NFAT5	ENST00000354436.6	TSL:1	c.1785A>T	p.Pro595Pro	synonymous	Exon 11 of 14	ENSP00000346420.2	O94916-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457332 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724704

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33350

American (AMR) AF: 0.00 AC: 0 AN: 44152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.00 AC: 0 AN: 84862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110054

Other (OTH) AF: 0.00 AC: 0 AN: 60220

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.70
PhyloP100		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs140085549; hg19: chr16-69724907;