NM_003332.4:c.*83C>T

Variant names:

• chr19-35904486-G-A
• rs14715
• NM_003332.4:c.*83C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003332.4(TYROBP):​c.*83C>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 0.00247 in 1,392,450 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (23 hom.)
• Consequence: TYROBP NM_003332.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.888

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-35904486-G-A is Benign according to our data. Variant chr19-35904486-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 328891.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 = 0.00995 (1515/152200) while in subpopulation AFR AF= 0.0331 (1372/41506). AF 95% confidence interval is 0.0316. There are 21 homozygotes in gnomad4. There are 695 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYROBP	NM_003332.4	c.*83C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000262629.9	NP_003323.1
HCST	NM_014266.4	c.*326G>A		downstream_gene_variant		ENST00000246551.9	NP_055081.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYROBP	ENST00000262629	c.*83C>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_003332.4	ENSP00000262629.3
HCST	ENST00000246551.9	c.*326G>A		downstream_gene_variant		1	NM_014266.4	ENSP00000246551.3

Frequencies

GnomAD3 genomes AF: 0.00992 AC: 1508 AN: 152082 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00485

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.00720

GnomAD3 exomes AF: 0.00310 AC: 637 AN: 205586 Hom.: 10 AF XY: 0.00224 AC XY: 248 AN XY: 110754

Gnomad AFR exome AF: 0.0359

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00326

Gnomad EAS exome AF: 0.0000633

Gnomad SAS exome AF: 0.000293

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000659

Gnomad OTH exome AF: 0.00168

GnomAD4 exome AF: 0.00156 AC: 1929 AN: 1240250 Hom.: 23 Cov.: 17 AF XY: 0.00136 AC XY: 849 AN XY: 623804

Gnomad4 AFR exome AF: 0.0349

Gnomad4 AMR exome AF: 0.00193

Gnomad4 ASJ exome AF: 0.00324

Gnomad4 EAS exome AF: 0.0000524

Gnomad4 SAS exome AF: 0.000339

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000611

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00995 AC: 1515 AN: 152200 Hom.: 21 Cov.: 32 AF XY: 0.00934 AC XY: 695 AN XY: 74420

Gnomad4 AFR AF: 0.0331

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.00427 Hom.: 2

Bravo AF: 0.0111

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 23, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.38
DANN	Benign	0.42

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

LitVar

Other links and lift over

dbSNP: rs14715; hg19: chr19-36395388;