chr9-90865069-G-A

Position:

chr9-90865069-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_003177.7(SYK):c.818G>A(p.Arg273His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

SYK
NM_003177.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.11

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 Benign. Variant got -7 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=0.01894036).

BS2

High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYK	NM_003177.7 linkuse as main transcript	c.818G>A	p.Arg273His	missense_variant	6/14	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.818G>A	p.Arg273His	missense_variant	6/14	1	NM_003177.7	ENSP00000364907.4	P43405-1
SYK	ENST00000375746.1 linkuse as main transcript	c.818G>A	p.Arg273His	missense_variant	6/14	1		ENSP00000364898.1	P43405-1
SYK	ENST00000375747.5 linkuse as main transcript	c.818G>A	p.Arg273His	missense_variant	6/13	1		ENSP00000364899.1	P43405-2
SYK	ENST00000375751.8 linkuse as main transcript	c.818G>A	p.Arg273His	missense_variant	6/13	1		ENSP00000364904.4	P43405-2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152138

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:

0.000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000175

AC:

AN:

251488

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000657

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000992

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000112

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74334

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:

0.000942

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000365

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Aug 10, 2024

The c.818G>A (p.R273H) alteration is located in exon 6 (coding exon 5) of the SYK gene. This alteration results from a G to A substitution at nucleotide position 818, causing the arginine (R) at amino acid position 273 to be replaced by a histidine (H). 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

0.083

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.53

DEOGEN2

Benign

0.23

T;.;.;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.72

.;.;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.019

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.20

N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.080

N;N;N;N

REVEL

Benign

0.058

Sift

Benign

0.55

T;T;T;T

Sift4G

Benign

0.19

T;T;T;T

Polyphen

0.0050

B;B;B;B

Vest4

0.27

MVP

0.77

MPC

0.95

ClinPred

0.020

GERP RS

2.5

Varity_R

0.015

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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