chr19-35904357-A-AC

Position:

• chr19-35904357-A-AC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_014266.4(HCST):​c.*202dup variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00697 in 798,538 control chromosomes in the GnomAD database, including 220 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (153 hom., cov: 31)
  • Exomes 𝑓: 0.0029 (67 hom.)
• Consequence: HCST NM_014266.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.123

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 19-35904357-A-AC is Benign according to our data. Variant chr19-35904357-A-AC is described in ClinVar as [Benign]. Clinvar id is 1238245.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCST	NM_014266.4	c.*202dup		3_prime_UTR_variant	4/4	ENST00000246551.9	NP_055081.1
TYROBP	NM_003332.4			downstream_gene_variant		ENST00000262629.9	NP_003323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCST	ENST00000246551.9	c.*202dup		3_prime_UTR_variant	4/4	1	NM_014266.4	ENSP00000246551	P2
TYROBP	ENST00000262629.9			downstream_gene_variant		1	NM_003332.4	ENSP00000262629	P4

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3661 AN: 151592 Hom.: 152 Cov.: 31

Gnomad AFR AF: 0.0835

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000627

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0130

GnomAD3 exomes AF: 0.00547 AC: 774 AN: 141520 Hom.: 30 AF XY: 0.00431 AC XY: 326 AN XY: 75566

Gnomad AFR exome AF: 0.0802

Gnomad AMR exome AF: 0.00557

Gnomad ASJ exome AF: 0.00106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000441

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000358

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00294 AC: 1904 AN: 646828 Hom.: 67 Cov.: 8 AF XY: 0.00237 AC XY: 810 AN XY: 341702

Gnomad4 AFR exome AF: 0.0772

Gnomad4 AMR exome AF: 0.00698

Gnomad4 ASJ exome AF: 0.00141

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000109

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000181

Gnomad4 OTH exome AF: 0.00624

GnomAD4 genome AF: 0.0241 AC: 3662 AN: 151710 Hom.: 153 Cov.: 31 AF XY: 0.0233 AC XY: 1727 AN XY: 74102

Gnomad4 AFR AF: 0.0833

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000627

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0134 Hom.: 12

Bravo AF: 0.0277

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

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: rs142104996; hg19: chr19-36395259;