Variant 19-35904661-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0420

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:

TYROBP (HGNC:):

TYROBP links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYROBP	NM_003332.4 linkuse as main transcript	c.277-27T>G		intron_variant		ENST00000262629.9	NP_003323.1	O43914-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYROBP	ENST00000262629.9 linkuse as main transcript	c.277-27T>G		intron_variant		1	NM_003332.4	ENSP00000262629.3		O43914-1

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1805

AN:

152126

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00713

AC:

1699

AN:

238404

Hom.:

AF XY:

0.00641

AC XY:

826

AN XY:

128916

show subpopulations

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 SAS exome

AF:

0.00596

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.:

Cov.:

AF XY:

0.00316

AC XY:

2284

AN XY:

722840

show subpopulations

Gnomad4 AFR exome

AF:

0.0334

Gnomad4 AMR exome

AF:

0.00349

Gnomad4 ASJ exome

AF:

0.0130

Gnomad4 EAS exome

AF:

0.0417

Gnomad4 SAS exome

AF:

0.00560

Gnomad4 FIN exome

AF:

0.000132

Gnomad4 NFE exome

AF:

0.000547

Gnomad4 OTH exome

AF:

0.00554

GnomAD4 genome

AF:

0.0119

AC:

1809

AN:

152244

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

863

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0340

Gnomad4 AMR

AF:

0.00549

Gnomad4 ASJ

AF:

0.0124

Gnomad4 EAS

AF:

0.0326

Gnomad4 SAS

AF:

0.00746

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00664

Alfa

AF:

0.00713

Hom.:

Bravo

AF:

0.0138

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

8.2

DANN

Benign

0.80

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over