rs8110231

Variant names:

• chr19-35905132-C-T
• rs8110231
• NM_003332.4:c.277-498G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003332.4(TYROBP):​c.277-498G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0723 in 152,230 control chromosomes in the GnomAD database, including 961 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.072 (961 hom., cov: 31)
• Consequence: TYROBP NM_003332.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYROBP	NM_003332.4	c.277-498G>A		intron_variant	Intron 4 of 4	ENST00000262629.9	NP_003323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYROBP	ENST00000262629.9	c.277-498G>A		intron_variant	Intron 4 of 4	1	NM_003332.4	ENSP00000262629.3

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10934 AN: 152112 Hom.: 938 Cov.: 31

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0328

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.0401

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.0616

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0723 AC: 11000 AN: 152230 Hom.: 961 Cov.: 31 AF XY: 0.0696 AC XY: 5180 AN XY: 74436

African (AFR) AF: 0.208 AC: 8647 AN: 41506

American (AMR) AF: 0.0327 AC: 500 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3472

East Asian (EAS) AF: 0.102 AC: 526 AN: 5178

South Asian (SAS) AF: 0.0395 AC: 191 AN: 4834

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10608

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0113 AC: 768 AN: 68032

Other (OTH) AF: 0.0610 AC: 129 AN: 2116

Alfa AF: 0.0444 Hom.: 128

Bravo AF: 0.0814

Asia WGS AF: 0.0760 AC: 263 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.40
DANN	Benign	0.64
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs8110231; hg19: chr19-36396034;