19-47021150-A-G

Variant names:

• chr19-47021150-A-G
• rs1214089110
• NM_002517.4:c.103A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002517.4(NPAS1):​c.103A>G​(p.Lys35Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000762 in 1,442,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: NPAS1 NM_002517.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27

Genes affected

NPAS1 (HGNC:7894): (neuronal PAS domain protein 1) The protein encoded by this gene is a member of the basic helix-loop-helix (bHLH)-PAS family of transcription factors. Studies of a related mouse gene suggest that it functions in neurons. The exact function of this gene is unclear, but it may play protective or modulatory roles during late embryogenesis and postnatal development. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.163097).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPAS1	NM_002517.4	c.103A>G	p.Lys35Glu	missense_variant	Exon 2 of 12	ENST00000602212.6	NP_002508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPAS1	ENST00000602212.6	c.103A>G	p.Lys35Glu	missense_variant	Exon 2 of 12	1	NM_002517.4	ENSP00000469142.1
NPAS1	ENST00000449844.6	c.103A>G	p.Lys35Glu	missense_variant	Exon 1 of 11	1		ENSP00000405290.1
NPAS1	ENST00000602189.5	c.-171+1153A>G		intron_variant	Intron 1 of 9	5		ENSP00000472679.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000762 AC: 11 AN: 1442698 Hom.: 0 Cov.: 33 AF XY: 0.00000558 AC XY: 4 AN XY: 717092

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000996

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000471 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.103A>G (p.K35E) alteration is located in exon 1 (coding exon 1) of the NPAS1 gene. This alteration results from a A to G substitution at nucleotide position 103, causing the lysine (K) at amino acid position 35 to be replaced by a glutamic acid (E). 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.54	.;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.25	.;N
REVEL	Benign	0.066
Sift	Benign	0.036	.;D
Sift4G	Benign	0.34	T;T
Polyphen		0.43	B;B
Vest4		0.45
MutPred		0.23		Loss of ubiquitination at K35 (P = 0.0041);Loss of ubiquitination at K35 (P = 0.0041);
MVP		0.17
MPC		0.95
ClinPred		0.33	T
GERP RS		3.0
Varity_R		0.18
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs1214089110; hg19: chr19-47524407;