rs386833839

Positions:

• chr19-35907559-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_003332.4(TYROBP):​c.116G>A​(p.Ser39Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TYROBP NM_003332.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.55

Genes affected

TYROBP (HGNC:12449): (transmembrane immune signaling adaptor TYROBP) This gene encodes a transmembrane signaling polypeptide which contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. The encoded protein may associate with the killer-cell inhibitory receptor (KIR) family of membrane glycoproteins and may act as an activating signal transduction element. This protein may bind zeta-chain (TCR) associated protein kinase 70kDa (ZAP-70) and spleen tyrosine kinase (SYK) and play a role in signal transduction, bone modeling, brain myelination, and inflammation. Mutations within this gene have been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), also known as Nasu-Hakola disease. Its putative receptor, triggering receptor expressed on myeloid cells 2 (TREM2), also causes PLOSL. Multiple alternative transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-35907559-C-T is Pathogenic according to our data. Variant chr19-35907559-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56394.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYROBP	NM_003332.4	c.116G>A	p.Ser39Asn	missense_variant	3/5	ENST00000262629.9	NP_003323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYROBP	ENST00000262629.9	c.116G>A	p.Ser39Asn	missense_variant	3/5	1	NM_003332.4	ENSP00000262629	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0086	T;.;.;T;.
Eigen	Benign	0.075
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.62	D;D;D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.5	.;.;.;M;M
MutationTaster	Benign	0.91	N;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.060	.;.;N;N;.
REVEL	Uncertain	0.30
Sift	Benign	0.30	.;.;T;T;.
Sift4G	Benign	0.91	T;T;T;T;T
Polyphen		0.76	.;.;.;P;P
Vest4		0.64
MutPred		0.50		.;Loss of disorder (P = 0.0698);.;Loss of disorder (P = 0.0698);Loss of disorder (P = 0.0698);
MVP		0.81
MPC		0.68
ClinPred		0.77	D
GERP RS		4.0
Varity_R		0.20
gMVP		0.67

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

Other links and lift over

dbSNP: rs386833839; hg19: chr19-36398461;