chr19-35904544-T-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 328892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYROBP	NM_003332.4	MANE Select	c.*25A>C		3_prime_UTR	Exon 5 of 5	NP_003323.1
	TYROBP	NR_033390.2		n.394A>C		non_coding_transcript_exon	Exon 4 of 4
	TYROBP	NM_198125.3		c.*25A>C		3_prime_UTR	Exon 5 of 5	NP_937758.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYROBP	ENST00000262629.9	TSL:1 MANE Select	c.*25A>C		3_prime_UTR	Exon 5 of 5	ENSP00000262629.3
	TYROBP	ENST00000544690.6	TSL:1	c.*25A>C		3_prime_UTR	Exon 4 of 4	ENSP00000445332.1
	TYROBP	ENST00000424586.7	TSL:1	c.*25A>C		3_prime_UTR	Exon 4 of 4	ENSP00000402371.3

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

GnomAD2 exomes AF: 0.0359 AC: 8949 AN: 248940 AF XY: 0.0325

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 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

African (AFR) AF: 0.218 AC: 7289 AN: 33430

American (AMR) AF: 0.0180 AC: 804 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 1149 AN: 26066

East Asian (EAS) AF: 0.109 AC: 4327 AN: 39672

South Asian (SAS) AF: 0.0333 AC: 2855 AN: 85836

European-Finnish (FIN) AF: 0.00459 AC: 244 AN: 53200

Middle Eastern (MID) AF: 0.0510 AC: 294 AN: 5766

European-Non Finnish (NFE) AF: 0.0107 AC: 11862 AN: 1111008

Other (OTH) AF: 0.0340 AC: 2052 AN: 60322

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

African (AFR) AF: 0.208 AC: 8620 AN: 41406

American (AMR) AF: 0.0325 AC: 496 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3470

East Asian (EAS) AF: 0.102 AC: 526 AN: 5180

South Asian (SAS) AF: 0.0396 AC: 191 AN: 4824

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10612

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0113 AC: 769 AN: 68004

Other (OTH) AF: 0.0611 AC: 129 AN: 2112

Alfa AF: 0.0288 Hom.: 990

Bravo AF: 0.0814

Asia WGS AF: 0.0770 AC: 265 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.9
DANN	Benign	0.76
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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