4-139043288-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_012118.4(NOCT):c.405T>C(p.Asp135=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00631 in 1,614,160 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0065 (50 hom.)
• Consequence: NOCT NM_012118.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.52

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 4-139043288-T-C is Benign according to our data. Variant chr4-139043288-T-C is described in ClinVar as [Benign]. Clinvar id is 770156.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00645 (9431/1461860) while in subpopulation AMR AF= 0.0309 (1384/44722). AF 95% confidence interval is 0.0296. There are 50 homozygotes in gnomad4_exome. There are 4541 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOCT	NM_012118.4	c.405T>C	p.Asp135=	synonymous_variant	2/3	ENST00000280614.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOCT	ENST00000280614.4	c.405T>C	p.Asp135=	synonymous_variant	2/3	1	NM_012118.4	P1
NOCT	ENST00000515616.1	n.217T>C		non_coding_transcript_exon_variant	1/2	1
NOCT	ENST00000630479.1	c.405T>C	p.Asp135=	synonymous_variant, NMD_transcript_variant	2/3	5
ELF2	ENST00000515489.1	n.273-14939A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00500 AC: 761 AN: 152182 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00689

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00848 AC: 2132 AN: 251476 Hom.: 27 AF XY: 0.00746 AC XY: 1014 AN XY: 135912

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.0342

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.00643

Gnomad OTH exome AF: 0.00880

GnomAD4 exome AF: 0.00645 AC: 9431 AN: 1461860 Hom.: 50 Cov.: 32 AF XY: 0.00624 AC XY: 4541 AN XY: 727232

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.0309

Gnomad4 ASJ exome AF: 0.00360

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000974

Gnomad4 FIN exome AF: 0.00472

Gnomad4 NFE exome AF: 0.00657

Gnomad4 OTH exome AF: 0.00449

GnomAD4 genome AF: 0.00500 AC: 761 AN: 152300 Hom.: 6 Cov.: 31 AF XY: 0.00473 AC XY: 352 AN XY: 74482

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.00691

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00568 Hom.: 1

Bravo AF: 0.00595

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00516

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 29, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.12
Dann	Benign	0.47

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: rs75806201; hg19: chr4-139964442;