11-66423839-A-C

Variant names:

• chr11-66423839-A-C
• rs76159120
• NM_178864.4:c.949A>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_178864.4(NPAS4):​c.949A>C​(p.Met317Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000413 in 1,607,886 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. M317V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (9 hom.)
• Consequence: NPAS4 NM_178864.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.169
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075536966).
• BS2: High AC in GnomAd4 at 49 AD gene.

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.949A>C	p.Met317Leu	missense	Exon 7 of 8	NP_849195.2	Q8IUM7-1
	NPAS4	NM_001318804.1		c.319A>C	p.Met107Leu	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.949A>C	p.Met317Leu	missense	Exon 7 of 8	ENSP00000311196.2	Q8IUM7-1
	NPAS4	ENST00000525148.1	TSL:1	n.*134A>C		non_coding_transcript_exon	Exon 6 of 7	ENSP00000433135.1	Q8IUM7-3
	NPAS4	ENST00000525148.1	TSL:1	n.*134A>C		3_prime_UTR	Exon 6 of 7	ENSP00000433135.1	Q8IUM7-3

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152106 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00887

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000641 AC: 158 AN: 246338 AF XY: 0.000579

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00850

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000422 AC: 615 AN: 1455662 Hom.: 9 Cov.: 32 AF XY: 0.000434 AC XY: 314 AN XY: 723712

African (AFR) AF: 0.00 AC: 0 AN: 33304

American (AMR) AF: 0.0000226 AC: 1 AN: 44204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25592

East Asian (EAS) AF: 0.0145 AC: 575 AN: 39648

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108448

Other (OTH) AF: 0.000632 AC: 38 AN: 60138

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152224 Hom.: 1 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74436

African (AFR) AF: 0.00 AC: 0 AN: 41532

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00889 AC: 46 AN: 5172

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000261 Hom.: 1

Bravo AF: 0.000249

ExAC AF: 0.000618 AC: 75

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Benign	0.77
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.17
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.049
Sift	Benign	0.18	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.42		Loss of disorder (P = 0.2888)
MVP		0.21
MPC		0.24
ClinPred		0.0097	T
GERP RS		-0.64
Varity_R		0.083
gMVP		0.13
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76159120; hg19: chr11-66191310;