chr19-35907559-C-T

Variant names:

• chr19-35907559-C-T
• rs386833839
• NM_003332.4:c.116G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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. 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
• Publications: 1 publications found

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]

TYROBP Gene-Disease associations (from GenCC):

• polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 56394.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003332.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYROBP	NM_003332.4	MANE Select	c.116G>A	p.Ser39Asn	missense	Exon 3 of 5	NP_003323.1	O43914-1
	TYROBP	NM_198125.3		c.116G>A	p.Ser39Asn	missense	Exon 3 of 5	NP_937758.1	O43914-2
	TYROBP	NM_001173514.2		c.83G>A	p.Ser28Asn	missense	Exon 2 of 4	NP_001166985.1	O43914-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYROBP	ENST00000262629.9	TSL:1 MANE Select	c.116G>A	p.Ser39Asn	missense	Exon 3 of 5	ENSP00000262629.3	O43914-1
	TYROBP	ENST00000589517.1	TSL:1	c.116G>A	p.Ser39Asn	missense	Exon 3 of 5	ENSP00000468447.1	O43914-2
	TYROBP	ENST00000544690.6	TSL:1	c.83G>A	p.Ser28Asn	missense	Exon 2 of 4	ENSP00000445332.1	O43914-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.075
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.060	N
REVEL	Uncertain	0.30
Sift	Benign	0.30	T
Sift4G	Benign	0.91	T
Polyphen		0.76	P
Vest4		0.64
MutPred		0.50		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
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs386833839; hg19: chr19-36398461;