19-35907232-C-T

Variant names:

• chr19-35907232-C-T
• rs386833842
• NM_003332.4:c.262G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003332.4(TYROBP):​c.262G>A​(p.Glu88Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000623 in 1,605,712 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TYROBP NM_003332.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.80
• Publications: 3 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), Genomics England PanelApp, Ambry Genetics, PanelApp Australia
• polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYROBP	NM_003332.4	MANE Select	c.262G>A	p.Glu88Lys	missense	Exon 4 of 5	NP_003323.1
	TYROBP	NM_198125.3		c.259G>A	p.Glu87Lys	missense	Exon 4 of 5	NP_937758.1
	TYROBP	NM_001173514.2		c.229G>A	p.Glu77Lys	missense	Exon 3 of 4	NP_001166985.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYROBP	ENST00000262629.9	TSL:1 MANE Select	c.262G>A	p.Glu88Lys	missense	Exon 4 of 5	ENSP00000262629.3
	TYROBP	ENST00000589517.1	TSL:1	c.259G>A	p.Glu87Lys	missense	Exon 4 of 5	ENSP00000468447.1
	TYROBP	ENST00000544690.6	TSL:1	c.229G>A	p.Glu77Lys	missense	Exon 3 of 4	ENSP00000445332.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152086 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000852 AC: 2 AN: 234816 AF XY: 0.00000789

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000189

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1453626 Hom.: 0 Cov.: 33 AF XY: 0.00000277 AC XY: 2 AN XY: 722262

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 42546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.00 AC: 0 AN: 84962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000722 AC: 8 AN: 1108568

Other (OTH) AF: 0.00 AC: 0 AN: 60136

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152086 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74276

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.54
Sift	Benign	0.10	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.42		Gain of MoRF binding (P = 0.0116)
MVP		0.90
MPC		0.89
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.41
gMVP		0.69
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs386833842; hg19: chr19-36398134;