chr4-139043286-G-A

Variant names:

• chr4-139043286-G-A
• rs371381290
• NM_012118.4:c.403G>A

Variant summary

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

The NM_012118.4(NOCT):​c.403G>A​(p.Asp135Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. D135H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NOCT NM_012118.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• Publications: 0 publications found

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:3317): (E74 like ETS transcription factor 2) Enables DNA-binding transcription factor activity, RNA polymerase II-specific and sequence-specific double-stranded DNA binding activity. Involved in negative regulation of transcription, DNA-templated; positive regulation of transcription, DNA-templated; and regulation of transcription by RNA polymerase II. Located in cytosol and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

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=0.06889582).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012118.4. 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
	NOCT	NM_012118.4	MANE Select	c.403G>A	p.Asp135Asn	missense	Exon 2 of 3	NP_036250.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOCT	ENST00000280614.4	TSL:1 MANE Select	c.403G>A	p.Asp135Asn	missense	Exon 2 of 3	ENSP00000280614.2	Q9UK39
	NOCT	ENST00000515616.1	TSL:1	n.215G>A		non_coding_transcript_exon	Exon 1 of 2
	NOCT	ENST00000866809.1		c.191-1353G>A		intron	N/A	ENSP00000536868.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	N
PhyloP100		1.5
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.054
Sift	Benign	0.45	T
Sift4G	Benign	0.55	T
Polyphen		0.0010	B
Vest4		0.046
MutPred		0.37		Loss of phosphorylation at T134 (P = 0.0968)
MVP		0.082
MPC		0.30
ClinPred		0.30	T
GERP RS		5.0
Varity_R		0.12
gMVP		0.32
Mutation Taster		=95/5	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: rs371381290; hg19: chr4-139964440;