4-139044947-G-A

Position:

• chr4-139044947-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012118.4(NOCT):​c.769G>A​(p.Ala257Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NOCT NM_012118.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.85

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOCT	NM_012118.4	c.769G>A	p.Ala257Thr	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.769G>A	p.Ala257Thr	missense_variant	3/3	1	NM_012118.4	ENSP00000280614	P1
NOCT	ENST00000515616.1	n.581G>A		non_coding_transcript_exon_variant	2/2	1
NOCT	ENST00000630479.1	c.*505-615G>A		intron_variant, NMD_transcript_variant		5		ENSP00000486546
ELF2	ENST00000515489.1	n.272+15377C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

May 09, 2023

The c.769G>A (p.A257T) alteration is located in exon 3 (coding exon 3) of the NOCT gene. This alteration results from a G to A substitution at nucleotide position 769, causing the alanine (A) at amino acid position 257 to be replaced by a threonine (T). 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	0.74
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.74	D
MetaSVM	Uncertain	-0.037	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.52
Sift	Benign	0.095	T
Sift4G	Benign	0.17	T
Polyphen		0.97	D
Vest4		0.60
MutPred		0.48		Loss of sheet (P = 0.0817);
MVP		0.47
MPC		0.48
ClinPred		0.87	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.64

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: chr4-139966101;