chr9-90865096-C-T

Variant names:

• chr9-90865096-C-T
• rs201994789
• NM_003177.7:c.845C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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: Splicing: ADA: 0.0003323
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.667

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]

ACMG classification

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
SYK	NM_003177.7	c.845C>T	p.Ala282Val	missense_variant, splice_region_variant	Exon 6 of 14	ENST00000375754.9	NP_003168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYK	ENST00000375754.9	c.845C>T	p.Ala282Val	missense_variant, splice_region_variant	Exon 6 of 14	1	NM_003177.7	ENSP00000364907.4
SYK	ENST00000375746.1	c.845C>T	p.Ala282Val	missense_variant, splice_region_variant	Exon 6 of 14	1		ENSP00000364898.1
SYK	ENST00000375747.5	c.845C>T	p.Ala282Val	missense_variant, splice_region_variant	Exon 6 of 13	1		ENSP00000364899.1
SYK	ENST00000375751.8	c.845C>T	p.Ala282Val	missense_variant, splice_region_variant	Exon 6 of 13	1		ENSP00000364904.4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152110 Hom.: 0 Cov.: 32

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

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

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

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

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

Other links and lift over

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