11-66421345-T-C

Variant names:

• chr11-66421345-T-C
• NM_178864.4:c.166T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_178864.4(NPAS4):​c.166T>C​(p.Phe56Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NPAS4 NM_178864.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.43

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPAS4	NM_178864.4	c.166T>C	p.Phe56Leu	missense_variant	Exon 1 of 8	ENST00000311034.7	NP_849195.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPAS4	ENST00000311034.7	c.166T>C	p.Phe56Leu	missense_variant	Exon 1 of 8	1	NM_178864.4	ENSP00000311196.2
NPAS4	ENST00000525148.1	n.166T>C		non_coding_transcript_exon_variant	Exon 1 of 7	1		ENSP00000433135.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.166T>C (p.F56L) alteration is located in exon 1 (coding exon 1) of the NPAS4 gene. This alteration results from a T to C substitution at nucleotide position 166, causing the phenylalanine (F) at amino acid position 56 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	.;D
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.2	.;D
REVEL	Uncertain	0.33
Sift	Benign	0.22	.;T
Sift4G	Pathogenic	0.0	.;D
Polyphen		0.43	.;B
Vest4		0.47
MutPred		0.40		Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);
MVP		0.52
MPC		3.1
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.43
gMVP		0.88

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-66188816;