4-55435202-A-G

Variant names:

• chr4-55435202-A-G
• rs1801260
• NM_004898.4:c.*213T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004898.4(CLOCK):​c.*213T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 587,320 control chromosomes in the GnomAD database, including 21,892 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 0.25 (4961 hom., cov: 32)
  • Exomes 𝑓: 0.27 (16931 hom.)
• Consequence: CLOCK NM_004898.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.802
• Publications: 328 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004898.4. 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.*213T>C		3_prime_UTR	Exon 23 of 23	NP_004889.1
	CLOCK	NM_001267843.2		c.*213T>C		3_prime_UTR	Exon 24 of 24	NP_001254772.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLOCK	ENST00000513440.6	TSL:1 MANE Select	c.*213T>C		3_prime_UTR	Exon 23 of 23	ENSP00000426983.1
	CLOCK	ENST00000309964.8	TSL:1	c.*213T>C		3_prime_UTR	Exon 22 of 22	ENSP00000308741.4
	CLOCK	ENST00000381322.5	TSL:1	c.*213T>C		3_prime_UTR	Exon 24 of 24	ENSP00000370723.1

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37470 AN: 152032 Hom.: 4955 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.0993

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.246

GnomAD4 exome AF: 0.272 AC: 118169 AN: 435170 Hom.: 16931 Cov.: 4 AF XY: 0.278 AC XY: 63693 AN XY: 229406

African (AFR) AF: 0.179 AC: 2187 AN: 12234

American (AMR) AF: 0.218 AC: 4194 AN: 19218

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 3004 AN: 13032

East Asian (EAS) AF: 0.130 AC: 3735 AN: 28716

South Asian (SAS) AF: 0.359 AC: 16468 AN: 45868

European-Finnish (FIN) AF: 0.339 AC: 9873 AN: 29160

Middle Eastern (MID) AF: 0.228 AC: 413 AN: 1810

European-Non Finnish (NFE) AF: 0.276 AC: 71864 AN: 260366

Other (OTH) AF: 0.260 AC: 6431 AN: 24766

GnomAD4 genome AF: 0.246 AC: 37495 AN: 152150 Hom.: 4961 Cov.: 32 AF XY: 0.252 AC XY: 18704 AN XY: 74362

African (AFR) AF: 0.172 AC: 7143 AN: 41516

American (AMR) AF: 0.234 AC: 3571 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 820 AN: 3468

East Asian (EAS) AF: 0.0991 AC: 513 AN: 5174

South Asian (SAS) AF: 0.371 AC: 1792 AN: 4826

European-Finnish (FIN) AF: 0.356 AC: 3769 AN: 10582

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19049 AN: 67980

Other (OTH) AF: 0.245 AC: 517 AN: 2114

Alfa AF: 0.261 Hom.: 21891

Bravo AF: 0.226

Asia WGS AF: 0.261 AC: 908 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.3
DANN	Benign	0.71
PhyloP100		0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1801260; hg19: chr4-56301369; COSMIC: COSV59401751;