rs7260613

Variant names:

• chr19-35906543-G-A
• rs7260613
• NM_003332.4:c.276+675C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-35906543-G-A
• chr19-35906543-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003332.4(TYROBP):​c.276+675C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 151,980 control chromosomes in the GnomAD database, including 2,151 homozygotes. 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 0.11 (2151 hom., cov: 31)
• Consequence: TYROBP NM_003332.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.221
• Publications: 3 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]

TYROBP Gene-Disease associations (from GenCC):

• polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, PanelApp Australia
• polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYROBP	NM_003332.4	c.276+675C>T		intron_variant	Intron 4 of 4	ENST00000262629.9	NP_003323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYROBP	ENST00000262629.9	c.276+675C>T		intron_variant	Intron 4 of 4	1	NM_003332.4	ENSP00000262629.3

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17427 AN: 151862 Hom.: 2150 Cov.: 31

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.0566

Gnomad ASJ AF: 0.0527

Gnomad EAS AF: 0.0399

Gnomad SAS AF: 0.0553

Gnomad FIN AF: 0.0435

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0828

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.115 AC: 17439 AN: 151980 Hom.: 2151 Cov.: 31 AF XY: 0.113 AC XY: 8407 AN XY: 74312

African (AFR) AF: 0.314 AC: 13012 AN: 41402

American (AMR) AF: 0.0564 AC: 862 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0527 AC: 183 AN: 3470

East Asian (EAS) AF: 0.0400 AC: 207 AN: 5174

South Asian (SAS) AF: 0.0551 AC: 266 AN: 4828

European-Finnish (FIN) AF: 0.0435 AC: 459 AN: 10560

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0327 AC: 2223 AN: 67968

Other (OTH) AF: 0.0819 AC: 172 AN: 2100

Alfa AF: 0.0626 Hom.: 311

Bravo AF: 0.125

Asia WGS AF: 0.0590 AC: 205 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.9
DANN	Benign	0.64
PhyloP100		0.22
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: rs7260613; hg19: chr19-36397445;