NM_178864.4:c.605G>A

Variant names:

• chr11-66422848-G-A
• rs759912439
• NM_178864.4:c.605G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_178864.4(NPAS4):​c.605G>A​(p.Gly202Asp) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G202V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPAS4 NM_178864.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.38
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29583746).

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.605G>A	p.Gly202Asp	missense	Exon 4 of 8	NP_849195.2	Q8IUM7-1
	NPAS4	NM_001318804.1		c.85G>A	p.Val29Ile	missense	Exon 4 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.605G>A	p.Gly202Asp	missense	Exon 4 of 8	ENSP00000311196.2	Q8IUM7-1
	NPAS4	ENST00000525148.1	TSL:1	n.605G>A		non_coding_transcript_exon	Exon 4 of 7	ENSP00000433135.1	Q8IUM7-3
	NPAS4	ENST00000524617.1	TSL:3	n.-36G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 250488 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.093
Sift	Benign	0.037	D
Sift4G	Benign	0.36	T
Polyphen		0.95	P
Vest4		0.78
MutPred		0.37		Loss of glycosylation at P203 (P = 0.0975)
MVP		0.70
MPC		0.99
ClinPred		0.88	D
GERP RS		5.3
Varity_R		0.088
gMVP		0.45
Mutation Taster		=72/28	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: rs759912439; hg19: chr11-66190319;