chr4-55432133-G-A

Variant names:

• chr4-55432133-G-A
• rs10462028
• NM_004898.4:c.*3282C>T

Variant summary

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

The NM_004898.4(CLOCK):​c.*3282C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 152,014 control chromosomes in the GnomAD database, including 6,463 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 0.28 (6463 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLOCK NM_004898.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0690
• Publications: 28 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.*3282C>T		3_prime_UTR_variant	Exon 23 of 23	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.*3282C>T		3_prime_UTR_variant	Exon 23 of 23	1	NM_004898.4	ENSP00000426983.1
CLOCK	ENST00000309964.8	c.*3282C>T		3_prime_UTR_variant	Exon 22 of 22	1		ENSP00000308741.4
TMEM165	ENST00000608091.1	c.406+7490G>A		intron_variant	Intron 3 of 3	3		ENSP00000476531.1
TMEM165	ENST00000506103.2	n.*270+7490G>A		intron_variant	Intron 2 of 2	3		ENSP00000476621.1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42561 AN: 151896 Hom.: 6455 Cov.: 33

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.270

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

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) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.280 AC: 42586 AN: 152014 Hom.: 6463 Cov.: 33 AF XY: 0.284 AC XY: 21130 AN XY: 74300

African (AFR) AF: 0.182 AC: 7545 AN: 41480

American (AMR) AF: 0.259 AC: 3962 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 870 AN: 3472

East Asian (EAS) AF: 0.100 AC: 519 AN: 5172

South Asian (SAS) AF: 0.399 AC: 1921 AN: 4814

European-Finnish (FIN) AF: 0.395 AC: 4168 AN: 10544

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.334 AC: 22681 AN: 67950

Other (OTH) AF: 0.268 AC: 565 AN: 2108

Alfa AF: 0.303 Hom.: 2906

Bravo AF: 0.258

Asia WGS AF: 0.268 AC: 933 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.9
DANN	Benign	0.58
PhyloP100		-0.069
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: rs10462028; hg19: chr4-56298300;