11-66422141-C-T

Variant names:

• chr11-66422141-C-T
• rs765449671
• NM_178864.4:c.197C>T

Variant summary

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

The NM_001318804.1(NPAS4):​c.-324C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NPAS4 NM_001318804.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.01
• Publications: 1 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=0.15318483).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318804.1. 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.197C>T	p.Thr66Met	missense	Exon 2 of 8	NP_849195.2	Q8IUM7-1
	NPAS4	NM_001318804.1		c.-324C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	NP_001305733.1	Q8IUM7
	NPAS4	NM_001318804.1		c.-324C>T		5_prime_UTR	Exon 2 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.197C>T	p.Thr66Met	missense	Exon 2 of 8	ENSP00000311196.2	Q8IUM7-1
	NPAS4	ENST00000525148.1	TSL:1	n.197C>T		non_coding_transcript_exon	Exon 2 of 7	ENSP00000433135.1	Q8IUM7-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251122 AF XY: 0.0000221

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461742 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	T
Eigen	Benign	0.033
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.93	L
PhyloP100		2.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.060
Sift	Benign	0.13	T
Sift4G	Benign	0.10	T
Polyphen		0.61	P
Vest4		0.12
MutPred		0.38		Gain of stability (P = 0.0061)
MVP		0.63
MPC		0.52
ClinPred		0.33	T
GERP RS		4.8
Varity_R		0.039
gMVP		0.59
Mutation Taster		=92/8	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: rs765449671; hg19: chr11-66189612; COSMIC: COSV60648925; COSMIC: COSV60648925;