TYROBP p.Asp32His

Variant names:

• chr19-35907581-C-G
• NM_003332.4:c.95-1G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-35907581-C-G
• chr19-35907579-ATC-GTG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_003332.4(TYROBP):​c.95-1G>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TYROBP NM_003332.4 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.42
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.39473686 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.8, offset of 7, new splice context is: ccctgtgctgcacattgcAGttg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

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.95-1G>C		splice_acceptor intron	N/A	NP_003323.1	O43914-1
	TYROBP	NM_198125.3		c.95-1G>C		splice_acceptor intron	N/A	NP_937758.1	O43914-2
	TYROBP	NM_001173514.2		c.62-1G>C		splice_acceptor intron	N/A	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.95-1G>C		splice_acceptor intron	N/A	ENSP00000262629.3	O43914-1
	TYROBP	ENST00000589517.1	TSL:1	c.95-1G>C		splice_acceptor intron	N/A	ENSP00000468447.1	O43914-2
	TYROBP	ENST00000544690.6	TSL:1	c.62-1G>C		splice_acceptor intron	N/A	ENSP00000445332.1	O43914-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Benign	-0.63
CADD	Pathogenic	29
DANN	Benign	0.84
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.64	D
PhyloP100		2.4
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.88		Position offset: -8
DS_AL_spliceai		0.95		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-36398483;