chr11-108158963-T-G

Variant names:

• chr11-108158963-T-G
• rs763893971
• NM_002519.3:c.4263A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002519.3(NPAT):​c.4263A>C​(p.Leu1421Phe) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L1421L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPAT NM_002519.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.165
• Publications: 0 publications found

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

ACMG classification

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=0.21264052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPAT	NM_002519.3	c.4263A>C	p.Leu1421Phe	missense_variant	Exon 18 of 18	ENST00000278612.9	NP_002510.2
NPAT	NM_001321307.1	c.4284A>C	p.Leu1428Phe	missense_variant	Exon 18 of 18		NP_001308236.1
NPAT	XM_011542854.3	c.4290A>C	p.Leu1430Phe	missense_variant	Exon 18 of 18		XP_011541156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPAT	ENST00000278612.9	c.4263A>C	p.Leu1421Phe	missense_variant	Exon 18 of 18	1	NM_002519.3	ENSP00000278612.8
NPAT	ENST00000850623.1	c.4263A>C	p.Leu1421Phe	missense_variant	Exon 18 of 18			ENSP00000520908.1
NPAT	ENST00000530859.1	n.1636A>C		non_coding_transcript_exon_variant	Exon 5 of 5	2
NPAT	ENST00000530926.1	n.420A>C		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L1421F variant (also known as c.4263A>C), located in coding exon 18 of the NPAT gene, results from an A to C substitution at nucleotide position 4263. The leucine at codon 1421 is replaced by phenylalanine, an amino acid with highly 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.17
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.10
Sift	Uncertain	0.025	D
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.20
MutPred		0.14		Loss of ubiquitination at K1418 (P = 0.0756);
MVP		0.54
MPC		0.34
ClinPred		0.81	D
GERP RS		0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.13
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs763893971; hg19: chr11-108029690;