11-116858173-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001366686.3(SIK3):c.3292G>A(p.Ala1098Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,614,060 control chromosomes in the GnomAD database, including 143 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (72 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (71 hom.)
• Consequence: SIK3 NM_001366686.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.867

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SIK3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015975535).
• BP6: Variant 11-116858173-C-T is Benign according to our data. Variant chr11-116858173-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 768487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIK3	NM_001366686.3	c.3292G>A	p.Ala1098Thr	missense_variant	21/25	ENST00000445177.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIK3	ENST00000445177.6	c.3292G>A	p.Ala1098Thr	missense_variant	21/25	5	NM_001366686.3	A2

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2668 AN: 152052 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.0584

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00521 AC: 1309 AN: 251212 Hom.: 34 AF XY: 0.00389 AC XY: 528 AN XY: 135766

Gnomad AFR exome AF: 0.0595

Gnomad AMR exome AF: 0.00581

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000608

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00218 AC: 3182 AN: 1461890 Hom.: 71 Cov.: 32 AF XY: 0.00195 AC XY: 1418 AN XY: 727248

Gnomad4 AFR exome AF: 0.0602

Gnomad4 AMR exome AF: 0.00586

Gnomad4 ASJ exome AF: 0.00452

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000399

Gnomad4 OTH exome AF: 0.00507

GnomAD4 genome AF: 0.0176 AC: 2674 AN: 152170 Hom.: 72 Cov.: 32 AF XY: 0.0167 AC XY: 1243 AN XY: 74388

Gnomad4 AFR AF: 0.0584

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00418 Hom.: 24

Bravo AF: 0.0200

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0525 AC: 231

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.00619 AC: 751

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SIK3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 14, 2018

- -

Spondyloepimetaphyseal dysplasia, Krakow type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	16
Dann	Benign	0.97
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.76	N;N
REVEL	Benign	0.024
Sift	Benign	0.28	T;T
Sift4G	Benign	0.32	T;T
Vest4		0.096
MVP		0.22
ClinPred		0.0037	T
GERP RS		0.74
Varity_R		0.047
gMVP		0.095

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs56247967; hg19: chr11-116728889; COSMIC: COSV99407763; COSMIC: COSV99407763;