9-90874749-A-G

Position:

chr9-90874749-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_003177.7(SYK):c.1081A>G(p.Lys361Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SYK
NM_003177.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.68

Variant links:

Genes affected

SYK (HGNC:11491): (spleen associated tyrosine kinase) This gene encodes a member of the family of non-receptor type Tyr protein kinases. This protein is widely expressed in hematopoietic cells and is involved in coupling activated immunoreceptors to downstream signaling events that mediate diverse cellular responses, including proliferation, differentiation, and phagocytosis. It is thought to be a modulator of epithelial cell growth and a potential tumour suppressor in human breast carcinomas. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

SYK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SYK. . Gene score misZ 2.9041 (greater than the threshold 3.09). Trascript score misZ 3.945 (greater than threshold 3.09). GenCC has associacion of gene with immunodeficiency 82 with systemic inflammation.

BP4

Computational evidence support a benign effect (MetaRNN=0.2223332).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYK	NM_003177.7 linkuse as main transcript	c.1081A>G	p.Lys361Glu	missense_variant	9/14	ENST00000375754.9	NP_003168.2	P43405-1A0A024R244

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SYK	ENST00000375754.9 linkuse as main transcript	c.1081A>G	p.Lys361Glu	missense_variant	9/14	1	NM_003177.7	ENSP00000364907.4	P43405-1
SYK	ENST00000375746.1 linkuse as main transcript	c.1081A>G	p.Lys361Glu	missense_variant	9/14	1		ENSP00000364898.1	P43405-1
SYK	ENST00000375747.5 linkuse as main transcript	c.1012A>G	p.Lys338Glu	missense_variant	8/13	1		ENSP00000364899.1	P43405-2
SYK	ENST00000375751.8 linkuse as main transcript	c.1012A>G	p.Lys338Glu	missense_variant	8/13	1		ENSP00000364904.4	P43405-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2024

The c.1081A>G (p.K361E) alteration is located in exon 9 (coding exon 8) of the SYK gene. This alteration results from a A to G substitution at nucleotide position 1081, causing the lysine (K) at amino acid position 361 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;.;.;T

Eigen

Benign

0.15

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.83

.;.;T;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.4

M;.;.;M

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Benign

0.27

Sift

Benign

0.076

T;T;T;T

Sift4G

Benign

0.44

T;T;T;T

Polyphen

0.44

B;P;P;B

Vest4

0.18

MutPred

0.39

Loss of methylation at K361 (P = 0.0097);.;.;Loss of methylation at K361 (P = 0.0097);

MVP

0.75

MPC

1.9

ClinPred

0.79

GERP RS

4.2

Varity_R

0.51

gMVP

0.67

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over