NM_178864.4:c.950T>A

Variant names:

• chr11-66423840-T-A
• NM_178864.4:c.950T>A

Variant summary

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

The NM_178864.4(NPAS4):​c.950T>A​(p.Met317Lys) 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. 16/22 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. M317V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPAS4 NM_178864.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.873
• Publications: 0 publications found

Genes affected

NPAS4 (HGNC:18983): (neuronal PAS domain protein 4) NXF is a member of the basic helix-loop-helix-PER (MIM 602260)-ARNT (MIM 126110)-SIM (see SIM2; MIM 600892) (bHLH-PAS) class of transcriptional regulators, which are involved in a wide range of physiologic and developmental events (Ooe et al., 2004 [PubMed 14701734]).[supplied by OMIM, Mar 2008]

NPAS4 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  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=0.06962934).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178864.4. 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
	NPAS4	NM_178864.4	MANE Select	c.950T>A	p.Met317Lys	missense	Exon 7 of 8	NP_849195.2	Q8IUM7-1
	NPAS4	NM_001318804.1		c.320T>A	p.Met107Lys	missense	Exon 6 of 7	NP_001305733.1	Q8IUM7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPAS4	ENST00000311034.7	TSL:1 MANE Select	c.950T>A	p.Met317Lys	missense	Exon 7 of 8	ENSP00000311196.2	Q8IUM7-1
	NPAS4	ENST00000525148.1	TSL:1	n.*135T>A		non_coding_transcript_exon	Exon 6 of 7	ENSP00000433135.1	Q8IUM7-3
	NPAS4	ENST00000525148.1	TSL:1	n.*135T>A		3_prime_UTR	Exon 6 of 7	ENSP00000433135.1	Q8IUM7-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.70
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.87
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.054
Sift	Benign	0.41	T
Sift4G	Benign	0.88	T
Polyphen		0.0	B
Vest4		0.33
MutPred		0.53		Gain of ubiquitination at M317 (P = 0.0203)
MVP		0.085
MPC		0.40
ClinPred		0.025	T
GERP RS		0.73
Varity_R		0.098
gMVP		0.24
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chr11-66191311;