9-90895479-A-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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 frequency of 0.557 in 1,602,760 control chromosomes in the GnomAD database, including 251,630 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as 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)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-90895479-A-T is Benign according to our data. Variant chr9-90895479-A-T is described in ClinVar as Benign. ClinVar VariationId is 2687942.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYK	NM_003177.7	MANE Select	c.1836-49A>T		intron	N/A	NP_003168.2
	SYK	NM_001174167.3		c.1836-49A>T		intron	N/A	NP_001167638.1
	SYK	NM_001135052.4		c.1767-49A>T		intron	N/A	NP_001128524.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYK	ENST00000375754.9	TSL:1 MANE Select	c.1836-49A>T		intron	N/A	ENSP00000364907.4
	SYK	ENST00000375746.1	TSL:1	c.1836-49A>T		intron	N/A	ENSP00000364898.1
	SYK	ENST00000375747.5	TSL:1	c.1767-49A>T		intron	N/A	ENSP00000364899.1

Frequencies

GnomAD3 genomes AF: 0.594 AC: 90211 AN: 151944 Hom.: 27411 Cov.: 32

Gnomad AFR AF: 0.722

Gnomad AMI AF: 0.542

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.602

Gnomad MID AF: 0.407

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.540

GnomAD2 exomes AF: 0.564 AC: 139040 AN: 246730 AF XY: 0.558

Gnomad AFR exome AF: 0.723

Gnomad AMR exome AF: 0.631

Gnomad ASJ exome AF: 0.481

Gnomad EAS exome AF: 0.407

Gnomad FIN exome AF: 0.589

Gnomad NFE exome AF: 0.540

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.553 AC: 802672 AN: 1450694 Hom.: 224186 Cov.: 27 AF XY: 0.553 AC XY: 399581 AN XY: 722202

African (AFR) AF: 0.727 AC: 24210 AN: 33300

American (AMR) AF: 0.630 AC: 28140 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 12676 AN: 26028

East Asian (EAS) AF: 0.397 AC: 15742 AN: 39608

South Asian (SAS) AF: 0.601 AC: 51682 AN: 85932

European-Finnish (FIN) AF: 0.582 AC: 30145 AN: 51824

Middle Eastern (MID) AF: 0.437 AC: 2504 AN: 5734

European-Non Finnish (NFE) AF: 0.548 AC: 605026 AN: 1103632

Other (OTH) AF: 0.542 AC: 32547 AN: 59996

GnomAD4 genome AF: 0.594 AC: 90294 AN: 152066 Hom.: 27444 Cov.: 32 AF XY: 0.593 AC XY: 44071 AN XY: 74324

African (AFR) AF: 0.722 AC: 29940 AN: 41492

American (AMR) AF: 0.585 AC: 8938 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 1666 AN: 3466

East Asian (EAS) AF: 0.400 AC: 2068 AN: 5172

South Asian (SAS) AF: 0.598 AC: 2879 AN: 4816

European-Finnish (FIN) AF: 0.602 AC: 6366 AN: 10572

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.540 AC: 36694 AN: 67950

Other (OTH) AF: 0.536 AC: 1130 AN: 2110

Alfa AF: 0.463 Hom.: 2207

Bravo AF: 0.596

Asia WGS AF: 0.501 AC: 1744 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 91% of patients studied by a panel of primary immunodeficiencies. Number of patients: 86. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.55
PhyloP100		-0.24
Mutation Taster		=6/94	disease causing

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

Other links and lift over

dbSNP: rs158689; hg19: chr9-93657761; COSMIC: COSV65324954;