4-139044899-C-T

Variant names:

• chr4-139044899-C-T
• NM_012118.4:c.721C>T

Variant summary

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

The NM_012118.4(NOCT):​c.721C>T​(p.Leu241Phe) 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 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NOCT NM_012118.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40
• 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 2 ACMG points.

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

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.721C>T	p.Leu241Phe	missense	Exon 3 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.721C>T	p.Leu241Phe	missense	Exon 3 of 3	ENSP00000280614.2	Q9UK39
	NOCT	ENST00000515616.1	TSL:1	n.533C>T		non_coding_transcript_exon	Exon 2 of 2
	NOCT	ENST00000866809.1		c.451C>T	p.Leu151Phe	missense	Exon 2 of 2	ENSP00000536868.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 0.00 AC: 0 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.43
Sift	Benign	0.051	T
Sift4G	Uncertain	0.043	D
Polyphen		0.99	D
Vest4		0.40
MutPred		0.62		Gain of catalytic residue at L241 (P = 0.0434)
MVP		0.33
MPC		0.77
ClinPred		0.94	D
GERP RS		5.5
Varity_R		0.49
gMVP		0.50
Mutation Taster		=49/51	disease causing

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

hg19: chr4-139966053;