chr19-35904486-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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=-0.88).
• BP6: Variant 19-35904486-G-A is Benign according to our data. Variant chr19-35904486-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYROBP	NM_003332.4	MANE Select	c.*83C>T		3_prime_UTR	Exon 5 of 5	NP_003323.1	O43914-1
	TYROBP	NM_198125.3		c.*83C>T		3_prime_UTR	Exon 5 of 5	NP_937758.1	O43914-2
	TYROBP	NM_001173514.2		c.*83C>T		3_prime_UTR	Exon 4 of 4	NP_001166985.1	O43914-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYROBP	ENST00000262629.9	TSL:1 MANE Select	c.*83C>T		3_prime_UTR	Exon 5 of 5	ENSP00000262629.3	O43914-1
	TYROBP	ENST00000544690.6	TSL:1	c.*83C>T		3_prime_UTR	Exon 4 of 4	ENSP00000445332.1	O43914-3
	TYROBP	ENST00000424586.7	TSL:1	c.*83C>T		3_prime_UTR	Exon 4 of 4	ENSP00000402371.3	X6RGC9

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

GnomAD2 exomes AF: 0.00310 AC: 637 AN: 205586 AF XY: 0.00224

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 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

African (AFR) AF: 0.0349 AC: 1021 AN: 29270

American (AMR) AF: 0.00193 AC: 76 AN: 39342

Ashkenazi Jewish (ASJ) AF: 0.00324 AC: 79 AN: 24402

East Asian (EAS) AF: 0.0000524 AC: 2 AN: 38182

South Asian (SAS) AF: 0.000339 AC: 27 AN: 79742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47872

Middle Eastern (MID) AF: 0.000565 AC: 3 AN: 5310

European-Non Finnish (NFE) AF: 0.000611 AC: 564 AN: 922920

Other (OTH) AF: 0.00295 AC: 157 AN: 53210

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

African (AFR) AF: 0.0331 AC: 1372 AN: 41506

American (AMR) AF: 0.00484 AC: 74 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68012

Other (OTH) AF: 0.00712 AC: 15 AN: 2106

Alfa AF: 0.00471 Hom.: 2

Bravo AF: 0.0111

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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	-0.88
CADD	Benign	0.38
DANN	Benign	0.42
PhyloP100		-0.89
Mutation Taster		=100/0	polymorphism

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: rs14715; hg19: chr19-36395388;