11-108159003-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002519.3(NPAT):c.4223G>C(p.Ser1408Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1408G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPAT NM_002519.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33

Genes affected

NPAT (HGNC:7896): (nuclear protein, coactivator of histone transcription) Enables protein C-terminus binding activity; transcription coactivator activity; and transcription corepressor activity. Involved in positive regulation of transcription by RNA polymerase II and regulation of transcription involved in G1/S transition of mitotic cell cycle. Located in Cajal body; Gemini of coiled bodies; and cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11991069).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPAT	NM_002519.3	c.4223G>C	p.Ser1408Thr	missense_variant	18/18	ENST00000278612.9
NPAT	NM_001321307.1	c.4244G>C	p.Ser1415Thr	missense_variant	18/18
NPAT	XM_011542854.3	c.4250G>C	p.Ser1417Thr	missense_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPAT	ENST00000278612.9	c.4223G>C	p.Ser1408Thr	missense_variant	18/18	1	NM_002519.3	P1
NPAT	ENST00000530859.1	n.1596G>C		non_coding_transcript_exon_variant	5/5	2
NPAT	ENST00000530926.1	n.380G>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000410 AC: 1 AN: 243870 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132770

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000906

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2022

The p.S1408T variant (also known as c.4223G>C), located in coding exon 18 of the NPAT gene, results from a G to C substitution at nucleotide position 4223. The serine at codon 1408 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	19
Dann	Benign	0.96
DEOGEN2	Benign	0.088	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.65	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.11
Sift	Benign	0.32	T
Sift4G	Benign	0.28	T
Polyphen		0.59	P
Vest4		0.23
MutPred		0.20		Gain of glycosylation at S1408 (P = 0.0118);
MVP		0.46
MPC		0.059
ClinPred		0.22	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.083
gMVP		0.022

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: rs778967998; hg19: chr11-108029730;