rs3817624

Variant names:

• chr19-35907997-C-T
• rs3817624
• NM_003332.4:c.61+171G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003332.4(TYROBP):​c.61+171G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0827 in 152,084 control chromosomes in the GnomAD database, including 595 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.083 (595 hom., cov: 31)
• Consequence: TYROBP NM_003332.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.648
• Publications: 10 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-35907997-C-T is Benign according to our data. Variant chr19-35907997-C-T is described in ClinVar as Benign. ClinVar VariationId is 1288066.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

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.61+171G>A		intron	N/A	NP_003323.1
	TYROBP	NM_198125.3		c.61+171G>A		intron	N/A	NP_937758.1
	TYROBP	NM_001173514.2		c.61+171G>A		intron	N/A	NP_001166985.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYROBP	ENST00000262629.9	TSL:1 MANE Select	c.61+171G>A		intron	N/A	ENSP00000262629.3
	TYROBP	ENST00000589517.1	TSL:1	c.61+171G>A		intron	N/A	ENSP00000468447.1
	TYROBP	ENST00000544690.6	TSL:1	c.61+171G>A		intron	N/A	ENSP00000445332.1

Frequencies

GnomAD3 genomes AF: 0.0828 AC: 12578 AN: 151966 Hom.: 594 Cov.: 31

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.0670

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0377

Gnomad EAS AF: 0.0319

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0994

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0978

Gnomad OTH AF: 0.0805

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

GnomAD4 genome AF: 0.0827 AC: 12583 AN: 152084 Hom.: 595 Cov.: 31 AF XY: 0.0843 AC XY: 6266 AN XY: 74332

African (AFR) AF: 0.0430 AC: 1787 AN: 41512

American (AMR) AF: 0.129 AC: 1972 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0377 AC: 131 AN: 3472

East Asian (EAS) AF: 0.0322 AC: 166 AN: 5160

South Asian (SAS) AF: 0.120 AC: 581 AN: 4828

European-Finnish (FIN) AF: 0.0994 AC: 1051 AN: 10574

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0978 AC: 6646 AN: 67966

Other (OTH) AF: 0.0830 AC: 175 AN: 2108

Alfa AF: 0.0903 Hom.: 1962

Bravo AF: 0.0829

Asia WGS AF: 0.0890 AC: 312 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.87
DANN	Benign	0.44
PhyloP100		-0.65
PromoterAI		-0.021	Neutral
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: rs3817624; hg19: chr19-36398899;