19-35904601-C-A

Variant names:

• chr19-35904601-C-A
• rs377005575
• NM_003332.4:c.310G>T

Variant summary

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

The NM_003332.4(TYROBP):​c.310G>T​(p.Asp104Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,930 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D104N) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: TYROBP NM_003332.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.57
• 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]

HCST (HGNC:16977): (hematopoietic cell signal transducer) This gene encodes a transmembrane signaling adaptor that contains a YxxM motif in its cytoplasmic domain. The encoded protein may form part of the immune recognition receptor complex with the C-type lectin-like receptor NKG2D. As part of this receptor complex, this protein may activate phosphatidylinositol 3-kinase dependent signaling pathways through its intracytoplasmic YxxM motif. This receptor complex may have a role in cell survival and proliferation by activation of NK and T cell responses. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYROBP	NM_003332.4	MANE Select	c.310G>T	p.Asp104Tyr	missense	Exon 5 of 5	NP_003323.1	O43914-1
	TYROBP	NM_198125.3		c.307G>T	p.Asp103Tyr	missense	Exon 5 of 5	NP_937758.1	O43914-2
	TYROBP	NM_001173514.2		c.277G>T	p.Asp93Tyr	missense	Exon 4 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.310G>T	p.Asp104Tyr	missense	Exon 5 of 5	ENSP00000262629.3	O43914-1
	TYROBP	ENST00000589517.1	TSL:1	c.307G>T	p.Asp103Tyr	missense	Exon 5 of 5	ENSP00000468447.1	O43914-2
	TYROBP	ENST00000544690.6	TSL:1	c.277G>T	p.Asp93Tyr	missense	Exon 4 of 4	ENSP00000445332.1	O43914-3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151930 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151930 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74216

African (AFR) AF: 0.00 AC: 0 AN: 41334

American (AMR) AF: 0.0000657 AC: 1 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.19	D
PhyloP100		1.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.56		Gain of MoRF binding (P = 0.0186)
MVP		0.90
MPC		0.94
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.38
gMVP		0.61
Mutation Taster		=73/27	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: rs377005575; hg19: chr19-36395503;