NM_003332.4:c.*25A>C

Variant names:

• chr19-35904544-T-G
• rs1802029
• NM_003332.4:c.*25A>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003332.4(TYROBP):​c.*25A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.026 in 1,611,984 control chromosomes in the GnomAD database, including 2,244 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (958 hom., cov: 31)
  • Exomes 𝑓: 0.021 (1286 hom.)
• Consequence: TYROBP NM_003332.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.153

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=-0.83).
• BP6: Variant 19-35904544-T-G is Benign according to our data. Variant chr19-35904544-T-G is described in ClinVar as [Benign]. Clinvar id is 328892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35904544-T-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYROBP	NM_003332.4	c.*25A>C		3_prime_UTR_variant	Exon 5 of 5	ENST00000262629.9	NP_003323.1
HCST	NM_014266.4	c.*384T>G		downstream_gene_variant		ENST00000246551.9	NP_055081.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYROBP	ENST00000262629	c.*25A>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_003332.4	ENSP00000262629.3
HCST	ENST00000246551.9	c.*384T>G		downstream_gene_variant		1	NM_014266.4	ENSP00000246551.3

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 10904 AN: 151974 Hom.: 935 Cov.: 31

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.0402

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.0617

GnomAD3 exomes AF: 0.0359 AC: 8949 AN: 248940 Hom.: 536 AF XY: 0.0325 AC XY: 4369 AN XY: 134598

Gnomad AFR exome AF: 0.213

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.0451

Gnomad EAS exome AF: 0.104

Gnomad SAS exome AF: 0.0326

Gnomad FIN exome AF: 0.00603

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.0293

GnomAD4 exome AF: 0.0211 AC: 30876 AN: 1459892 Hom.: 1286 Cov.: 30 AF XY: 0.0208 AC XY: 15130 AN XY: 726130

Gnomad4 AFR exome AF: 0.218

Gnomad4 AMR exome AF: 0.0180

Gnomad4 ASJ exome AF: 0.0441

Gnomad4 EAS exome AF: 0.109

Gnomad4 SAS exome AF: 0.0333

Gnomad4 FIN exome AF: 0.00459

Gnomad4 NFE exome AF: 0.0107

Gnomad4 OTH exome AF: 0.0340

GnomAD4 genome AF: 0.0721 AC: 10970 AN: 152092 Hom.: 958 Cov.: 31 AF XY: 0.0694 AC XY: 5163 AN XY: 74342

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.0325

Gnomad4 ASJ AF: 0.0360

Gnomad4 EAS AF: 0.102

Gnomad4 SAS AF: 0.0396

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.0611

Alfa AF: 0.0224 Hom.: 289

Bravo AF: 0.0814

Asia WGS AF: 0.0770 AC: 265 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: 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	-0.83
CADD	Benign	5.9
DANN	Benign	0.76

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: rs1802029; hg19: chr19-36395446; COSMIC: COSV52887757; COSMIC: COSV52887757;