9-90844052-G-C

Variant names:

• chr9-90844052-G-C
• rs796052158
• NM_003177.7:c.154G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003177.7(SYK):​c.154G>C​(p.Ala52Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. A52S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SYK NM_003177.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency 82 with systemic inflammation

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003177.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYK	NM_003177.7	MANE Select	c.154G>C	p.Ala52Pro	missense	Exon 2 of 14	NP_003168.2
	SYK	NM_001174167.3		c.154G>C	p.Ala52Pro	missense	Exon 2 of 14	NP_001167638.1
	SYK	NM_001135052.4		c.154G>C	p.Ala52Pro	missense	Exon 2 of 13	NP_001128524.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYK	ENST00000375754.9	TSL:1 MANE Select	c.154G>C	p.Ala52Pro	missense	Exon 2 of 14	ENSP00000364907.4
	SYK	ENST00000375746.1	TSL:1	c.154G>C	p.Ala52Pro	missense	Exon 2 of 14	ENSP00000364898.1
	SYK	ENST00000375747.5	TSL:1	c.154G>C	p.Ala52Pro	missense	Exon 2 of 13	ENSP00000364899.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.79
Sift	Benign	0.042	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.80		Loss of catalytic residue at A52 (P = 0.046)
MVP		0.93
MPC		0.81
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.87
gMVP		0.92
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs796052158; hg19: chr9-93606334;