rs374144427

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_003332.4(TYROBP):c.*85C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,374,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

TYROBP
NM_003332.4 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.24

Publications

0 publications found

Variant links:

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 links:

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]

HCST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000709 (108/152234) while in subpopulation EAS AF = 0.00444 (23/5186). AF 95% confidence interval is 0.00303. There are 0 homozygotes in GnomAd4. There are 60 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TYROBP	NM_003332.4	MANE Select	c.*85C>T	3_prime_UTR	Exon 5 of 5	NP_003323.1	O43914-1
TYROBP	NM_198125.3		c.*85C>T	3_prime_UTR	Exon 5 of 5	NP_937758.1	O43914-2
TYROBP	NM_001173514.2		c.*85C>T	3_prime_UTR	Exon 4 of 4	NP_001166985.1	O43914-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TYROBP	ENST00000262629.9	TSL:1 MANE Select	c.*85C>T	3_prime_UTR	Exon 5 of 5	ENSP00000262629.3	O43914-1
TYROBP	ENST00000544690.6	TSL:1	c.*85C>T	3_prime_UTR	Exon 4 of 4	ENSP00000445332.1	O43914-3
TYROBP	ENST00000424586.7	TSL:1	c.*85C>T	3_prime_UTR	Exon 4 of 4	ENSP00000402371.3	X6RGC9

Frequencies

GnomAD3 genomes

AF:

0.000703

AC:

107

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00191

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00442

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000514

AC:

104

AN:

202482

AF XY:

0.000477

show subpopulations

Gnomad AFR exome

AF:

0.00250

Gnomad AMR exome

AF:

0.0000700

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00326

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000569

Gnomad OTH exome

AF:

0.000753

GnomAD4 exome

AF:

0.000223

AC:

273

AN:

1222354

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

141

AN XY:

615410

show subpopulations

African (AFR)

AF:

0.00256

AC:

AN:

28954

American (AMR)

AF:

0.0000515

AC:

AN:

38866

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24300

East Asian (EAS)

AF:

0.00147

AC:

AN:

38090

South Asian (SAS)

AF:

0.000479

AC:

AN:

79258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47352

Middle Eastern (MID)

AF:

0.000190

AC:

AN:

5268

European-Non Finnish (NFE)

AF:

0.0000661

AC:

AN:

907588

Other (OTH)

AF:

0.000797

AC:

AN:

52678

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000709

AC:

108

AN:

152234

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00193

AC:

AN:

41520

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00444

AC:

AN:

5186

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000693

Hom.:

Bravo

AF:

0.000808

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.62

(source)

DANN

Benign

0.67

PhyloP100

-1.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over