9-90877564-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003177.7(SYK):c.1182-7C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,613,860 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (45 hom.)
• Consequence: SYK NM_003177.7 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006384
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.332

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 9-90877564-C-A is Benign according to our data. Variant chr9-90877564-C-A is described in ClinVar as [Benign]. Clinvar id is 776432.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0126 (1917/152180) while in subpopulation AFR AF= 0.0427 (1775/41522). AF 95% confidence interval is 0.0411. There are 40 homozygotes in gnomad4. There are 932 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1913 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYK	NM_003177.7	c.1182-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000375754.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYK	ENST00000375754.9	c.1182-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003177.7	P1
SYK	ENST00000375746.1	c.1182-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1
SYK	ENST00000375747.5	c.1113-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
SYK	ENST00000375751.8	c.1113-7C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1913 AN: 152062 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0428

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00359 AC: 900 AN: 251034 Hom.: 16 AF XY: 0.00260 AC XY: 353 AN XY: 135712

Gnomad AFR exome AF: 0.0438

Gnomad AMR exome AF: 0.00342

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00151 AC: 2208 AN: 1461680 Hom.: 45 Cov.: 33 AF XY: 0.00137 AC XY: 995 AN XY: 727142

Gnomad4 AFR exome AF: 0.0447

Gnomad4 AMR exome AF: 0.00443

Gnomad4 ASJ exome AF: 0.000650

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000209

Gnomad4 OTH exome AF: 0.00364

GnomAD4 genome AF: 0.0126 AC: 1917 AN: 152180 Hom.: 40 Cov.: 33 AF XY: 0.0125 AC XY: 932 AN XY: 74380

Gnomad4 AFR AF: 0.0427

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.000688 Hom.: 316

EpiCase AF: 0.000436

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	4.0
Dann	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.018
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: rs290223; hg19: chr9-93639846;