9-90874692-C-A

Position:

• chr9-90874692-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_003177.7(SYK):​c.1024C>A​(p.Pro342Thr) 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYK NM_003177.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.37

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SYK. . Gene score misZ 2.9041 (greater than the threshold 3.09). Trascript score misZ 3.945 (greater than threshold 3.09). GenCC has associacion of gene with immunodeficiency 82 with systemic inflammation.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804
• PP5: Variant 9-90874692-C-A is Pathogenic according to our data. Variant chr9-90874692-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 989387.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYK	NM_003177.7	c.1024C>A	p.Pro342Thr	missense_variant	9/14	ENST00000375754.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYK	ENST00000375754.9	c.1024C>A	p.Pro342Thr	missense_variant	9/14	1	NM_003177.7	P1
SYK	ENST00000375746.1	c.1024C>A	p.Pro342Thr	missense_variant	9/14	1		P1
SYK	ENST00000375747.5	c.955C>A	p.Pro319Thr	missense_variant	8/13	1
SYK	ENST00000375751.8	c.955C>A	p.Pro319Thr	missense_variant	8/13	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 82 with systemic inflammation Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 21, 2021

- -

Arthritis;C0009319:Colitis;C0021051:Immunodeficiency;C4048270:Decreased circulating antibody concentration;C5779628:Skin rash Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Aleixo Muise Laboratory, Hospital For Sick Children

Dec 10, 2020

de novo (from TRIO WES) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;.;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;.;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.6	M;.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Benign	0.26	T;T;T;T
Polyphen		1.0	D;D;D;D
Vest4		0.80
MutPred		0.29		Gain of glycosylation at P342 (P = 0.0563);.;.;Gain of glycosylation at P342 (P = 0.0563);
MVP		0.82
MPC		1.7
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.88
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs1827861920; hg19: chr9-93636974;