rs766372791

Variant names:

• chr19-35904621-T-C
• rs766372791
• NM_003332.4:c.290A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-35904621-T-C
• chr19-35904621-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003332.4(TYROBP):​c.290A>G​(p.Gln97Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TYROBP NM_003332.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.664
• 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]

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16945013).

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.290A>G	p.Gln97Arg	missense	Exon 5 of 5	NP_003323.1	O43914-1
	TYROBP	NM_198125.3		c.287A>G	p.Gln96Arg	missense	Exon 5 of 5	NP_937758.1	O43914-2
	TYROBP	NM_001173514.2		c.257A>G	p.Gln86Arg	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.290A>G	p.Gln97Arg	missense	Exon 5 of 5	ENSP00000262629.3	O43914-1
	TYROBP	ENST00000589517.1	TSL:1	c.287A>G	p.Gln96Arg	missense	Exon 5 of 5	ENSP00000468447.1	O43914-2
	TYROBP	ENST00000544690.6	TSL:1	c.257A>G	p.Gln86Arg	missense	Exon 4 of 4	ENSP00000445332.1	O43914-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461044 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726668

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 85956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111670

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Benign	0.72
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.62	T
PhyloP100		0.66
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.33	N
REVEL	Uncertain	0.40
Sift	Benign	0.52	T
Sift4G	Benign	0.43	T
Polyphen		0.59	P
Vest4		0.26
MutPred		0.34		Gain of MoRF binding (P = 0.0556)
MVP		0.77
MPC		0.60
ClinPred		0.69	D
GERP RS		3.1
Varity_R		0.069
gMVP		0.23
Mutation Taster		=85/15	polymorphism

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: rs766372791; hg19: chr19-36395523;