chr9-90865096-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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: Splicing: ADA: 0.00001828
• Clinical Significance: Not reported in ClinVar
• 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 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
SYK	NM_003177.7	c.845C>A	p.Ala282Glu	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>A	p.Ala282Glu	missense_variant, splice_region_variant	Exon 6 of 14	1	NM_003177.7	ENSP00000364907.4
SYK	ENST00000375746.1	c.845C>A	p.Ala282Glu	missense_variant, splice_region_variant	Exon 6 of 14	1		ENSP00000364898.1
SYK	ENST00000375747.5	c.845C>A	p.Ala282Glu	missense_variant, splice_region_variant	Exon 6 of 13	1		ENSP00000364899.1
SYK	ENST00000375751.8	c.845C>A	p.Ala282Glu	missense_variant, splice_region_variant	Exon 6 of 13	1		ENSP00000364904.4

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

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

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

Other links and lift over

dbSNP: rs201994789; hg19: chr9-93627378;