chr9-90895479-A-C

Variant names:

• chr9-90895479-A-C
• rs158689
• NM_003177.7:c.1836-49A>C

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The NM_003177.7(SYK):c.1836-49A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000138 (AC=2) in the gnomAD database across 1,452,100 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000003. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SYK NM_003177.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.245
• 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), PanelApp Australia

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000003 — very rare for AD/XL gene (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SYK NM_003177.7	MANE Select	c.1836-49A>C	intron	Intron 13 of 13	Prot: NP_003168.2
	SYK NM_001174167.3		c.1836-49A>C	intron	Intron 13 of 13	Prot: NP_001167638.1 UniProt:
	SYK NM_001135052.4		c.1767-49A>C	intron	Intron 12 of 12	Prot: NP_001128524.1 UniProt:

SYK NM_003177.7

MANE Select

HGVSc / HGVSpc.1836-49A>C

Exon rankIntron 13 of 13

intron

Prot: NP_003168.2

SYK NM_001174167.3

HGVSc / HGVSpc.1836-49A>C

Exon rankIntron 13 of 13

intron

Prot: NP_001167638.1UniProt: P43405-1

SYK NM_001135052.4

HGVSc / HGVSpc.1767-49A>C

Exon rankIntron 12 of 12

intron

Prot: NP_001128524.1UniProt: P43405-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SYK ENST00000375754.9	TSL:1MANE Select	c.1836-49A>C	intron	Intron 13 of 13	Prot: ENSP00000364907.4 UniProt:
	SYK ENST00000375746.1	TSL:1	c.1836-49A>C	intron	Intron 13 of 13	Prot: ENSP00000364898.1 UniProt:
	SYK ENST00000375747.5	TSL:1	c.1767-49A>C	intron	Intron 12 of 12	Prot: ENSP00000364899.1 UniProt:

SYK ENST00000375754.9

TSL:1MANE Select

HGVSc / HGVSpc.1836-49A>C

Exon rankIntron 13 of 13

intron

Prot: ENSP00000364907.4UniProt: P43405-1

SYK ENST00000375746.1

TSL:1

HGVSc / HGVSpc.1836-49A>C

Exon rankIntron 13 of 13

intron

Prot: ENSP00000364898.1UniProt: P43405-1

SYK ENST00000375747.5

TSL:1

HGVSc / HGVSpc.1767-49A>C

Exon rankIntron 12 of 12

intron

Prot: ENSP00000364899.1UniProt: P43405-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 0.00000138	AC:2	Hom:0	AN:1452100	Cov:27
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	67788	0.00000751	1	133140

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	1.6
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.18
GPN-Star LLR	N/A	2.5
GPN-Star score	N/A	-2.4
PhyloP100	Benign	-0.24

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs158689;

hg19: chr9-93657761;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar