chr4-55434518-C-T

Variant names:

• chr4-55434518-C-T
• rs3749474
• ENST00000511124.1:n.1890G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000511124.1(CLOCK):​n.1890G>A variant causes a non coding transcript exon 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 ENST00000511124.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21
• Publications: 78 publications found

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]

TMEM165 Gene-Disease associations (from GenCC):

• TMEM165-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000511124.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLOCK	NM_004898.4	MANE Select	c.*897G>A		3_prime_UTR	Exon 23 of 23	NP_004889.1
	CLOCK	NM_001267843.2		c.*897G>A		3_prime_UTR	Exon 24 of 24	NP_001254772.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLOCK	ENST00000511124.1	TSL:1	n.1890G>A		non_coding_transcript_exon	Exon 7 of 7
	CLOCK	ENST00000513440.6	TSL:1 MANE Select	c.*897G>A		3_prime_UTR	Exon 23 of 23	ENSP00000426983.1
	CLOCK	ENST00000309964.8	TSL:1	c.*897G>A		3_prime_UTR	Exon 22 of 22	ENSP00000308741.4

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.394 AC: 156 AN: 396

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.250 AC: 1 AN: 4

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

African (AFR) AF: 0.198 AC: 8191 AN: 41376

American (AMR) AF: 0.438 AC: 6683 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1447 AN: 3464

East Asian (EAS) AF: 0.585 AC: 3017 AN: 5158

South Asian (SAS) AF: 0.439 AC: 2110 AN: 4806

European-Finnish (FIN) AF: 0.394 AC: 4120 AN: 10444

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.362 AC: 24610 AN: 67908

Other (OTH) AF: 0.341 AC: 718 AN: 2104

Alfa AF: 0.338 Hom.: 2336

Bravo AF: 0.337

Asia WGS AF: 0.474 AC: 1647 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	8.4
DANN	Benign	0.80
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs3749474; hg19: chr4-56300685;