Genetic Variant NM_002519.3:c.4225T>G (chr11-108159001-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002519.3(NPAT):c.4225T>G(p.Ser1409Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. S1409L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NPAT
NM_002519.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.58

Publications

0 publications found

Variant links:

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]

NPAT Gene-Disease associations (from GenCC):

colorectal cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

NPAT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11256504).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002519.3. 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
	NPAT	NM_002519.3	MANE Select	c.4225T>G	p.Ser1409Ala	missense	Exon 18 of 18	NP_002510.2	Q14207
	NPAT	NM_001321307.1		c.4246T>G	p.Ser1416Ala	missense	Exon 18 of 18	NP_001308236.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPAT	ENST00000278612.9	TSL:1 MANE Select	c.4225T>G	p.Ser1409Ala	missense	Exon 18 of 18	ENSP00000278612.8	Q14207
NPAT	ENST00000935790.1		c.4252T>G	p.Ser1418Ala	missense	Exon 18 of 18	ENSP00000605849.1
NPAT	ENST00000850623.1		c.4225T>G	p.Ser1409Ala	missense	Exon 18 of 18	ENSP00000520908.1	Q14207

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1454872

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33380

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39510

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109000

Other (OTH)

AF:

0.00

AC:

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.062

Eigen

Benign

-0.11

Eigen_PC

Benign

0.027

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.47

M_CAP

Benign

0.0068

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.63

PhyloP100

3.6

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.3

REVEL

Benign

0.049

Sift

Benign

0.15

Sift4G

Benign

0.47

Polyphen

0.21

Vest4

0.090

MutPred

0.13

Loss of phosphorylation at S1409 (P = 0.0089)

MVP

0.29

MPC

0.055

ClinPred

0.60

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.056

gMVP

0.035

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over