rs201994789

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003177.7(SYK):​c.845C>A​(p.Ala282Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,524 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A282V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SYK
NM_003177.7 missense, splice_region

Scores

19
Splicing: ADA: 0.00001828
2

Clinical Significance

Not reported in ClinVar

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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.057869166).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYKNM_003177.7 linkc.845C>A p.Ala282Glu 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>A p.Ala282Glu missense_variant, splice_region_variant Exon 6 of 14 1 NM_003177.7 ENSP00000364907.4 P43405-1
SYKENST00000375746.1 linkc.845C>A p.Ala282Glu missense_variant, splice_region_variant Exon 6 of 14 1 ENSP00000364898.1 P43405-1
SYKENST00000375747.5 linkc.845C>A p.Ala282Glu missense_variant, splice_region_variant Exon 6 of 13 1 ENSP00000364899.1 P43405-2
SYKENST00000375751.8 linkc.845C>A p.Ala282Glu missense_variant, splice_region_variant Exon 6 of 13 1 ENSP00000364904.4 P43405-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251486
Hom.:
0
AF XY:
0.00
AC XY:
0
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:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461524
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
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:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
12
DANN
Benign
0.43
DEOGEN2
Benign
0.13
T;.;.;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.055
N
LIST_S2
Benign
0.20
.;.;T;T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.055
T;T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.90
L;L;L;L
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.0
N;N;N;N
REVEL
Benign
0.050
Sift
Benign
0.79
T;T;T;T
Sift4G
Benign
0.60
T;T;T;T
Polyphen
0.037
B;B;B;B
Vest4
0.29
MutPred
0.35
Loss of MoRF binding (P = 0.0594);Loss of MoRF binding (P = 0.0594);Loss of MoRF binding (P = 0.0594);Loss of MoRF binding (P = 0.0594);
MVP
0.67
MPC
0.75
ClinPred
0.027
T
GERP RS
-2.9
Varity_R
0.054
gMVP
0.39

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000018
dbscSNV1_RF
Benign
0.094
SpliceAI score (max)
0.11
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; API