Variant 9-90844061-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_003177.7(SYK):c.163G>A(p.Val55Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000067 in 1,612,238 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

SYK
NM_003177.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.55

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYK	NM_003177.7 link	c.163G>A	p.Val55Met	missense_variant	2/14	ENST00000375754.9	NP_003168.2	P43405-1A0A024R244

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYK	ENST00000375754.9 link	c.163G>A	p.Val55Met	missense_variant	2/14	1	NM_003177.7	ENSP00000364907.4		P43405-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000523

AC:

AN:

248384

Hom.:

AF XY:

0.0000596

AC XY:

AN XY:

134260

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.0000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000651

AC:

AN:

1460004

Hom.:

Cov.:

AF XY:

0.0000702

AC XY:

AN XY:

726210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000765

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Immunodeficiency 82 with systemic inflammation

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Feb 15, 2024

This sequence variant is a single nucleotide substitution (G>A) at position 163 of the coding sequence of the SYK gene that results in a valine to methionine amino acid change at residue 55 of the spleen associated tyrosine kinase protein. This residue falls in the N-terminal Src homology 2 (SH2) domain (UniProt). This variant is absent from ClinVar and has not been observed in individuals affected by a SYK-related disorder in the published literature, to our knowledge. This variant is present in 108 of 1612238 alleles (0.0067%) in the gnomAD v4.0.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Val55 residue at this position is well conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;.;.;D

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

.;.;D;D

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.42

T;T;T;T

MetaSVM

Uncertain

0.56

MutationAssessor

Uncertain

2.8

M;M;M;M

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.46

N;N;N;N

REVEL

Uncertain

0.60

Sift

Benign

0.15

T;T;T;T

Sift4G

Benign

0.20

T;T;T;T

Polyphen

1.0

D;D;D;D

Vest4

0.14

MVP

0.90

MPC

0.63

ClinPred

0.44

GERP RS

5.0

Varity_R

0.12

gMVP

0.62

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over