9-90864655-A-C

Position:

• chr9-90864655-A-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003177.7(SYK):​c.784A>C​(p.Ile262Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,614,124 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00081 (13 hom.)
• Consequence: SYK NM_003177.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.08

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 -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0060960352).
• BP6: Variant 9-90864655-A-C is Benign according to our data. Variant chr9-90864655-A-C is described in ClinVar as [Benign]. Clinvar id is 776431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00609 (927/152296) while in subpopulation AFR AF= 0.0201 (834/41540). AF 95% confidence interval is 0.0189. There are 12 homozygotes in gnomad4. There are 450 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 927 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYK	NM_003177.7	c.784A>C	p.Ile262Leu	missense_variant	5/14	ENST00000375754.9	NP_003168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYK	ENST00000375754.9	c.784A>C	p.Ile262Leu	missense_variant	5/14	1	NM_003177.7	ENSP00000364907.4
SYK	ENST00000375746.1	c.784A>C	p.Ile262Leu	missense_variant	5/14	1		ENSP00000364898.1
SYK	ENST00000375747.5	c.784A>C	p.Ile262Leu	missense_variant	5/13	1		ENSP00000364899.1
SYK	ENST00000375751.8	c.784A>C	p.Ile262Leu	missense_variant	5/13	1		ENSP00000364904.4

Frequencies

GnomAD3 genomes AF: 0.00607 AC: 924 AN: 152178 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00183 AC: 461 AN: 251430 Hom.: 3 AF XY: 0.00141 AC XY: 191 AN XY: 135900

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000811 AC: 1185 AN: 1461828 Hom.: 13 Cov.: 30 AF XY: 0.000752 AC XY: 547 AN XY: 727222

Gnomad4 AFR exome AF: 0.0219

Gnomad4 AMR exome AF: 0.00311

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000136

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.00609 AC: 927 AN: 152296 Hom.: 12 Cov.: 33 AF XY: 0.00604 AC XY: 450 AN XY: 74488

Gnomad4 AFR AF: 0.0201

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00118 Hom.: 1

Bravo AF: 0.00688

ESP6500AA AF: 0.0161 AC: 71

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00189 AC: 229

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.11	T;.;.;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.60	.;.;T;T
MetaRNN	Benign	0.0061	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.18	N;N;N;N
REVEL	Benign	0.046
Sift	Benign	0.72	T;T;T;T
Sift4G	Benign	0.72	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.16
MVP		0.72
MPC		0.62
ClinPred		0.0082	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs112619650; hg19: chr9-93626937;