rs533556

Variant names:

• chr11-116870856-A-C
• rs533556
• NM_001366686.3:c.1738-455T>G

Variant summary

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

The NM_001366686.3(SIK3):​c.1738-455T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 152,018 control chromosomes in the GnomAD database, including 18,609 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 0.45 (18609 hom., cov: 31)
• Consequence: SIK3 NM_001366686.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.862
• Publications: 10 publications found

Genes affected

SIK3 (HGNC:29165): (SIK family kinase 3) Enables ATP binding activity; magnesium ion binding activity; and protein serine/threonine kinase activity. Involved in positive regulation of TORC1 signaling; positive regulation of TORC2 signaling; and protein phosphorylation. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SIK3 Gene-Disease associations (from GenCC):

• autism

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hearing loss disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• spondyloepimetaphyseal dysplasia, Krakow type

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

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 (NFE) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIK3	NM_001366686.3	c.1738-455T>G		intron_variant	Intron 13 of 24	ENST00000445177.6	NP_001353615.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIK3	ENST00000445177.6	c.1738-455T>G		intron_variant	Intron 13 of 24	5	NM_001366686.3	ENSP00000391295.2

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68395 AN: 151900 Hom.: 18614 Cov.: 31

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.797

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.537

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.627

Gnomad OTH AF: 0.490

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

GnomAD4 genome AF: 0.450 AC: 68383 AN: 152018 Hom.: 18609 Cov.: 31 AF XY: 0.442 AC XY: 32853 AN XY: 74280

African (AFR) AF: 0.162 AC: 6734 AN: 41502

American (AMR) AF: 0.459 AC: 7009 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.537 AC: 1864 AN: 3470

East Asian (EAS) AF: 0.230 AC: 1188 AN: 5166

South Asian (SAS) AF: 0.313 AC: 1505 AN: 4812

European-Finnish (FIN) AF: 0.533 AC: 5624 AN: 10544

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.627 AC: 42571 AN: 67944

Other (OTH) AF: 0.484 AC: 1023 AN: 2114

Alfa AF: 0.547 Hom.: 50500

Bravo AF: 0.435

Asia WGS AF: 0.233 AC: 813 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	5.1
DANN	Benign	0.76
PhyloP100		0.86
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: rs533556; hg19: chr11-116741572;