rs3749474

chr4-55434518-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_004898.4(CLOCK):c.*897G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 152,110 control chromosomes in the GnomAD database, including 9,387 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.34 (9354 hom., cov: 32)
  • Exomes 𝑓: 0.39 (33 hom.)
• Consequence: CLOCK NM_004898.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21

Genes affected

CLOCK (HGNC:2082): (clock circadian regulator) The protein encoded by this gene plays a central role in the regulation of circadian rhythms. The protein encodes a transcription factor of the basic helix-loop-helix (bHLH) family and contains DNA binding histone acetyltransferase activity. The encoded protein forms a heterodimer with ARNTL (BMAL1) that binds E-box enhancer elements upstream of Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes and activates transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting in a feedback loop with CLOCK/ARNTL complexes. Polymorphisms in this gene may be associated with behavioral changes in certain populations and with obesity and metabolic syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

TMEM165 (HGNC:30760): (transmembrane protein 165) This gene encodes a predicted transmembrane protein with a perinuclear Golgi-like distribution in fibroblasts. Mutations in this gene are associated with the autosomal recessive disorder congenital disorder of glycosylation, type IIk. Knockdown of this gene's expression causes decreased sialylation in HEK cells and suggests this gene plays a role in terminal Golgi glycosylation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLOCK	NM_004898.4	c.*897G>A		3_prime_UTR_variant	23/23	ENST00000513440.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLOCK	ENST00000513440.6	c.*897G>A		3_prime_UTR_variant	23/23	1	NM_004898.4	P1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51260 AN: 151592 Hom.: 9345 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.585

Gnomad SAS AF: 0.440

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.336

GnomAD4 exome AF: 0.393 AC: 157 AN: 400 Hom.: 33 Cov.: 0 AF XY: 0.413 AC XY: 100 AN XY: 242

Gnomad4 FIN exome AF: 0.394

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.338 AC: 51269 AN: 151710 Hom.: 9354 Cov.: 32 AF XY: 0.345 AC XY: 25597 AN XY: 74100

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.438

Gnomad4 ASJ AF: 0.418

Gnomad4 EAS AF: 0.585

Gnomad4 SAS AF: 0.439

Gnomad4 FIN AF: 0.394

Gnomad4 NFE AF: 0.362

Gnomad4 OTH AF: 0.341

Alfa AF: 0.341 Hom.: 2319

Bravo AF: 0.337

Asia WGS AF: 0.474 AC: 1647 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	8.4
Dann	Benign	0.80

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: rs3749474; hg19: chr4-56300685;