9-90874772-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_003177.7(SYK):c.1104G>T(p.Lys368Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYK NM_003177.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.85

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SYK
• BP4: Computational evidence support a benign effect (MetaRNN=0.049866706).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYK	NM_003177.7	c.1104G>T	p.Lys368Asn	missense_variant	9/14	ENST00000375754.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYK	ENST00000375754.9	c.1104G>T	p.Lys368Asn	missense_variant	9/14	1	NM_003177.7	P1
SYK	ENST00000375746.1	c.1104G>T	p.Lys368Asn	missense_variant	9/14	1		P1
SYK	ENST00000375747.5	c.1035G>T	p.Lys345Asn	missense_variant	8/13	1
SYK	ENST00000375751.8	c.1035G>T	p.Lys345Asn	missense_variant	8/13	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The c.1104G>T (p.K368N) alteration is located in exon 9 (coding exon 8) of the SYK gene. This alteration results from a G to T substitution at nucleotide position 1104, causing the lysine (K) at amino acid position 368 to be replaced by an asparagine (N). 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	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	0.025
Dann	Benign	0.73
DEOGEN2	Benign	0.11	T;.;.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.027	N
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.050	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.20	N;.;.;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.10	N;N;N;N
REVEL	Benign	0.091
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.40	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.061
MutPred		0.34		Loss of ubiquitination at K368 (P = 0.0103);.;.;Loss of ubiquitination at K368 (P = 0.0103);
MVP		0.61
MPC		0.73
ClinPred		0.073	T
GERP RS		-8.6
Varity_R		0.19
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-93637054;