4-139045404-A-G

Position:

• chr4-139045404-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012118.4(NOCT):​c.1226A>G​(p.Asn409Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NOCT NM_012118.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.44

Genes affected

NOCT (HGNC:14254): (nocturnin) The protein encoded by this gene is highly similar to Nocturnin, a gene identified as a circadian clock regulated gene in Xenopus laevis. This protein and Nocturnin protein share similarity with the C-terminal domain of a yeast transcription factor, carbon catabolite repression 4 (CCR4). The mRNA abundance of a similar gene in mouse has been shown to exhibit circadian rhythmicity, which suggests a role for this protein in clock function or as a circadian clock effector. [provided by RefSeq, Jul 2008]

ELF2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.074983925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOCT	NM_012118.4	c.1226A>G	p.Asn409Ser	missense_variant	3/3	ENST00000280614.4	NP_036250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOCT	ENST00000280614.4	c.1226A>G	p.Asn409Ser	missense_variant	3/3	1	NM_012118.4	ENSP00000280614.2
ELF2	ENST00000515489.1	n.272+14920T>C		intron_variant		2
NOCT	ENST00000630479.1	n.*505-158A>G		intron_variant		5		ENSP00000486546.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461816 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2024

The c.1226A>G (p.N409S) alteration is located in exon 3 (coding exon 3) of the NOCT gene. This alteration results from a A to G substitution at nucleotide position 1226, causing the asparagine (N) at amino acid position 409 to be replaced by a serine (S). 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	Benign	0.059
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.67
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.28	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.017
Sift	Benign	0.85	T
Sift4G	Benign	0.92	T
Polyphen		0.0050	B
Vest4		0.14
MutPred		0.29		Gain of disorder (P = 0.0391);
MVP		0.043
MPC		0.25
ClinPred		0.068	T
GERP RS		2.9
Varity_R		0.17
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-139966558;