4-55440643-A-C

Variant names:

• chr4-55440643-A-C
• rs3805148
• NM_004898.4:c.2105+1789T>G

Variant summary

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

The NM_004898.4(CLOCK):​c.2105+1789T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 152,150 control chromosomes in the GnomAD database, including 9,382 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 (9382 hom., cov: 33)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.691
• Publications: 22 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.2105+1789T>G		intron_variant	Intron 21 of 22	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.2105+1789T>G		intron_variant	Intron 21 of 22	1	NM_004898.4	ENSP00000426983.1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51383 AN: 152032 Hom.: 9373 Cov.: 33

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.584

Gnomad SAS AF: 0.440

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.336

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.338 AC: 51392 AN: 152150 Hom.: 9382 Cov.: 33 AF XY: 0.345 AC XY: 25691 AN XY: 74392

African (AFR) AF: 0.198 AC: 8223 AN: 41530

American (AMR) AF: 0.438 AC: 6697 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1451 AN: 3472

East Asian (EAS) AF: 0.583 AC: 3021 AN: 5178

South Asian (SAS) AF: 0.439 AC: 2119 AN: 4826

European-Finnish (FIN) AF: 0.395 AC: 4177 AN: 10572

Middle Eastern (MID) AF: 0.318 AC: 93 AN: 292

European-Non Finnish (NFE) AF: 0.362 AC: 24611 AN: 67978

Other (OTH) AF: 0.341 AC: 720 AN: 2110

Alfa AF: 0.332 Hom.: 1108

Bravo AF: 0.337

Asia WGS AF: 0.476 AC: 1654 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.3
DANN	Benign	0.76
PhyloP100		0.69
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: rs3805148; hg19: chr4-56306810;