chr9-90865096-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003177.7(SYK):​c.845C>T​(p.Ala282Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

SYK
NM_003177.7 missense, splice_region

Scores

19
Splicing: ADA: 0.0003323
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.667
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.032763064).
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYKNM_003177.7 linkc.845C>T p.Ala282Val missense_variant, splice_region_variant Exon 6 of 14 ENST00000375754.9 NP_003168.2 P43405-1A0A024R244

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SYKENST00000375754.9 linkc.845C>T p.Ala282Val missense_variant, splice_region_variant Exon 6 of 14 1 NM_003177.7 ENSP00000364907.4 P43405-1
SYKENST00000375746.1 linkc.845C>T p.Ala282Val missense_variant, splice_region_variant Exon 6 of 14 1 ENSP00000364898.1 P43405-1
SYKENST00000375747.5 linkc.845C>T p.Ala282Val missense_variant, splice_region_variant Exon 6 of 13 1 ENSP00000364899.1 P43405-2
SYKENST00000375751.8 linkc.845C>T p.Ala282Val missense_variant, splice_region_variant Exon 6 of 13 1 ENSP00000364904.4 P43405-2

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152110
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000283
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000636
AC:
16
AN:
251486
Hom.:
0
AF XY:
0.0000736
AC XY:
10
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000323
Gnomad NFE exome
AF:
0.0000615
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.0000322
AC:
47
AN:
1461524
Hom.:
0
Cov.:
31
AF XY:
0.0000330
AC XY:
24
AN XY:
727096
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.000337
Gnomad4 NFE exome
AF:
0.0000225
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152110
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74290
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000283
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000824
AC:
10
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 09, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.845C>T (p.A282V) alteration is located in exon 6 (coding exon 5) of the SYK gene. This alteration results from a C to T substitution at nucleotide position 845, causing the alanine (A) at amino acid position 282 to be replaced by a valine (V). 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
0.079
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
15
DANN
Benign
0.91
DEOGEN2
Benign
0.10
T;.;.;T
Eigen
Benign
-0.98
Eigen_PC
Benign
-0.97
FATHMM_MKL
Benign
0.019
N
LIST_S2
Benign
0.21
.;.;T;T
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.033
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.20
N;N;N;N
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.68
N;N;N;N
REVEL
Benign
0.057
Sift
Benign
0.33
T;T;T;T
Sift4G
Benign
0.65
T;T;T;T
Polyphen
0.0010
B;B;B;B
Vest4
0.22
MutPred
0.26
Loss of disorder (P = 0.0858);Loss of disorder (P = 0.0858);Loss of disorder (P = 0.0858);Loss of disorder (P = 0.0858);
MVP
0.62
MPC
0.62
ClinPred
0.035
T
GERP RS
-2.9
Varity_R
0.019
gMVP
0.18

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00033
dbscSNV1_RF
Benign
0.13
SpliceAI score (max)
0.12
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.

Other links and lift over

dbSNP: rs201994789; hg19: chr9-93627378; COSMIC: COSV65331383; API