19-35904661-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: -0.0420

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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 GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYROBP	NM_003332.4	c.277-27T>G		intron_variant		ENST00000262629.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYROBP	ENST00000262629.9	c.277-27T>G		intron_variant		1	NM_003332.4	P4

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

GnomAD3 exomes AF: 0.00713 AC: 1699 AN: 238404 Hom.: 20 AF XY: 0.00641 AC XY: 826 AN XY: 128916

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.: 79 Cov.: 30 AF XY: 0.00316 AC XY: 2284 AN XY: 722840

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.: 22 Cov.: 31 AF XY: 0.0116 AC XY: 863 AN XY: 74448

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.: 2

Bravo AF: 0.0138

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 09, 2020

- -

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

Other links and lift over

dbSNP: rs75330483; hg19: chr19-36395563; COSMIC: COSV52888420; COSMIC: COSV52888420;