chr19-35904466-A-T

Variant names:

• chr19-35904466-A-T
• rs777094340
• NM_003332.4:c.*103T>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_003332.4(TYROBP):​c.*103T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,217,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: TYROBP NM_003332.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.362
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000513 (78/151984) while in subpopulation NFE AF = 0.000603 (41/67966). AF 95% confidence interval is 0.000457. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYROBP	NM_003332.4	c.*103T>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000262629.9	NP_003323.1
HCST	NM_014266.4	c.*306A>T		downstream_gene_variant		ENST00000246551.9	NP_055081.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYROBP	ENST00000262629.9	c.*103T>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_003332.4	ENSP00000262629.3
HCST	ENST00000246551.9	c.*306A>T		downstream_gene_variant		1	NM_014266.4	ENSP00000246551.3

Frequencies

GnomAD3 genomes AF: 0.000514 AC: 78 AN: 151866 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00180

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000317 AC: 58 AN: 182730 AF XY: 0.000307

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00304

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00163

Gnomad NFE exome AF: 0.000129

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000244 AC: 260 AN: 1065796 Hom.: 0 Cov.: 14 AF XY: 0.000223 AC XY: 121 AN XY: 542402

African (AFR) AF: 0.00 AC: 0 AN: 25866

American (AMR) AF: 0.00 AC: 0 AN: 36722

Ashkenazi Jewish (ASJ) AF: 0.00348 AC: 81 AN: 23244

East Asian (EAS) AF: 0.00 AC: 0 AN: 36906

South Asian (SAS) AF: 0.00 AC: 0 AN: 75256

European-Finnish (FIN) AF: 0.00183 AC: 81 AN: 44192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5026

European-Non Finnish (NFE) AF: 0.000110 AC: 85 AN: 771094

Other (OTH) AF: 0.000274 AC: 13 AN: 47490

GnomAD4 genome AF: 0.000513 AC: 78 AN: 151984 Hom.: 0 Cov.: 32 AF XY: 0.000512 AC XY: 38 AN XY: 74284

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.0000656 AC: 1 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00180 AC: 19 AN: 10570

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

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00151 Hom.: 0

Bravo AF: 0.000181

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.6
DANN	Benign	0.64
PhyloP100		0.36
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: rs777094340; hg19: chr19-36395368;