9-90895479-A-T

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Moderate

The NM_003177.7(SYK):c.1836-49A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.557 (AC=892,966) in the gnomAD database across 1,602,760 control chromosomes, including 251,630 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.719. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

• Frequency:
  • Genomes: 𝑓 0.59 (27444 hom., cov: 32)
  • Exomes 𝑓: 0.55 (224186 hom.)
• Consequence: SYK NM_003177.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.245
• Publications: 13 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: Benign. The variant received -14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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).
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.7194 — exceeds 5%% threshold (BA1 applied)

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>T	intron	Intron 13 of 13	Prot: NP_003168.2
	SYK NM_001174167.3		c.1836-49A>T	intron	Intron 13 of 13	Prot: NP_001167638.1 UniProt:
	SYK NM_001135052.4		c.1767-49A>T	intron	Intron 12 of 12	Prot: NP_001128524.1 UniProt:

SYK NM_003177.7

MANE Select

HGVSc / HGVSpc.1836-49A>T

Exon rankIntron 13 of 13

intron

Prot: NP_003168.2

SYK NM_001174167.3

HGVSc / HGVSpc.1836-49A>T

Exon rankIntron 13 of 13

intron

Prot: NP_001167638.1UniProt: P43405-1

SYK NM_001135052.4

HGVSc / HGVSpc.1767-49A>T

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>T	intron	Intron 13 of 13	Prot: ENSP00000364907.4 UniProt:
	SYK ENST00000375746.1	TSL:1	c.1836-49A>T	intron	Intron 13 of 13	Prot: ENSP00000364898.1 UniProt:
	SYK ENST00000375747.5	TSL:1	c.1767-49A>T	intron	Intron 12 of 12	Prot: ENSP00000364899.1 UniProt:

SYK ENST00000375754.9

TSL:1MANE Select

HGVSc / HGVSpc.1836-49A>T

Exon rankIntron 13 of 13

intron

Prot: ENSP00000364907.4UniProt: P43405-1

SYK ENST00000375746.1

TSL:1

HGVSc / HGVSpc.1836-49A>T

Exon rankIntron 13 of 13

intron

Prot: ENSP00000364898.1UniProt: P43405-1

SYK ENST00000375747.5

TSL:1

HGVSc / HGVSpc.1767-49A>T

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.594	AC:90211	Hom:27411	AN:151944	Cov:32
GnomAD2 exomes	AF: 0.564	AC:139040	Hom:	AN:246730	Cov:
GnomAD4 exome	AF: 0.553	AC:802672	Hom:224186	AN:1450694	Cov:27
GnomAD4 genome	AF: 0.594	AC:90294	Hom:27444	AN:152066	Cov:32
TOPMed (Bravo)	AF: 0.596	AC:157682	Hom:48121	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.483	AC:10791	Hom:3028	AN:22362	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.528	AC:1237	Hom:341	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.406	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.517	AC:155	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.592	AC:7703	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.501	AC:1744	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.438	AC:3166	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.472	AC:83	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.375	AC:46062	Hom:8816	AN:122710	Cov:
Turkish Variome	AF: 0.513	AC:3370	Hom:895	AN:6574	Cov:
UK10K	AF: 0.551	AC:4163	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.401	AC:3592	Hom:736	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.549 *	809	1474	0.556 *	3973	7144
BipEx(Bipolar disorder (including schizoaffective))	0.551	15660	28418	0.553	15958	28836
SCHEMA(Schizophrenia)	0.458	35452	77400	0.454	63005	138896

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	4.3
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.55
GPN-Star LLR	N/A	4.3
GPN-Star score	N/A	-0.61
Mutation Taster	N/A	6/94	disease causing
PhyloP100	Benign	-0.24

Showing 8 of 8 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;

COSMIC: COSV65324954;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar