rs75330483

Variant names:

• chr19-35904661-A-C
• rs75330483
• NM_003332.4:c.277-27T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003332.4(TYROBP):​c.277-27T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,606,250 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (79 hom.)
• Consequence: TYROBP NM_003332.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0420
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-35904661-A-C is Benign according to our data. Variant chr19-35904661-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1220182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0119 (1809/152244) while in subpopulation AFR AF = 0.034 (1412/41528). AF 95% confidence interval is 0.0325. There are 22 homozygotes in GnomAd4. There are 863 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

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.277-27T>G		intron	N/A	NP_003323.1	O43914-1
	TYROBP	NM_198125.3		c.274-27T>G		intron	N/A	NP_937758.1	O43914-2
	TYROBP	NM_001173514.2		c.244-27T>G		intron	N/A	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.277-27T>G		intron	N/A	ENSP00000262629.3	O43914-1
	TYROBP	ENST00000589517.1	TSL:1	c.274-27T>G		intron	N/A	ENSP00000468447.1	O43914-2
	TYROBP	ENST00000544690.6	TSL:1	c.244-27T>G		intron	N/A	ENSP00000445332.1	O43914-3

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1805 AN: 152126 Hom.: 22 Cov.: 31

Gnomad AFR AF: 0.0340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.0325

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00713 AC: 1699 AN: 238404 AF XY: 0.00641

Gnomad AFR exome AF: 0.0334

Gnomad AMR exome AF: 0.00290

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.0357

Gnomad FIN exome AF: 0.000144

Gnomad NFE exome AF: 0.000947

Gnomad OTH exome AF: 0.00774

GnomAD4 exome AF: 0.00324 AC: 4708 AN: 1454006 Hom.: 79 Cov.: 30 AF XY: 0.00316 AC XY: 2284 AN XY: 722840

African (AFR) AF: 0.0334 AC: 1116 AN: 33396

American (AMR) AF: 0.00349 AC: 153 AN: 43832

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 336 AN: 25908

East Asian (EAS) AF: 0.0417 AC: 1651 AN: 39622

South Asian (SAS) AF: 0.00560 AC: 477 AN: 85168

European-Finnish (FIN) AF: 0.000132 AC: 7 AN: 52936

Middle Eastern (MID) AF: 0.00511 AC: 29 AN: 5672

European-Non Finnish (NFE) AF: 0.000547 AC: 606 AN: 1107370

Other (OTH) AF: 0.00554 AC: 333 AN: 60102

GnomAD4 genome AF: 0.0119 AC: 1809 AN: 152244 Hom.: 22 Cov.: 31 AF XY: 0.0116 AC XY: 863 AN XY: 74448

African (AFR) AF: 0.0340 AC: 1412 AN: 41528

American (AMR) AF: 0.00549 AC: 84 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3470

East Asian (EAS) AF: 0.0326 AC: 169 AN: 5184

South Asian (SAS) AF: 0.00746 AC: 36 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68008

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00808 Hom.: 3

Bravo AF: 0.0138

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.2
DANN	Benign	0.80
PhyloP100		-0.042
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs75330483; hg19: chr19-36395563; COSMIC: COSV52888420; COSMIC: COSV52888420;