11-67991567-TC-TCC

Variant names:

• chr11-67991567-T-TC
• rs1288924599
• NM_030930.4:c.1772dupG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_030930.4(UNC93B1):​c.1772dupG​(p.Asp592ArgfsTer126) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G591G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000045 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UNC93B1 NM_030930.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.177
• Publications: 0 publications found

Genes affected

UNC93B1 (HGNC:13481): (unc-93 homolog B1, TLR signaling regulator) This gene encodes a protein that is involved in innate and adaptive immune response by regulating toll-like receptor signaling. The encoded protein traffics nucleotide sensing toll-like receptors to the endolysosome from the endoplasmic reticulum. Deficiency of the encoded protein has been associated with herpes simplex encephalitis. [provided by RefSeq, Feb 2014]

UNC93B1 Gene-Disease associations (from GenCC):

• herpes simplex encephalitis, susceptibility to, 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0123 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC93B1	NM_030930.4	c.1772dupG	p.Asp592ArgfsTer126	frameshift_variant	Exon 11 of 11	ENST00000227471.7	NP_112192.2
UNC93B1	XM_011545290.1	c.1361dupG	p.Asp455ArgfsTer126	frameshift_variant	Exon 9 of 9		XP_011543592.1
UNC93B1	XM_011545291.3	c.1217dupG	p.Asp407ArgfsTer126	frameshift_variant	Exon 8 of 8		XP_011543593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC93B1	ENST00000227471.7	c.1772dupG	p.Asp592ArgfsTer126	frameshift_variant	Exon 11 of 11	1	NM_030930.4	ENSP00000227471.3
UNC93B1	ENST00000525368.1	n.*250dupG		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000233 AC: 2 AN: 85660 AF XY: 0.0000208

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000453 AC: 6 AN: 1325104 Hom.: 0 Cov.: 30 AF XY: 0.00000461 AC XY: 3 AN XY: 651086

African (AFR) AF: 0.00 AC: 0 AN: 26388

American (AMR) AF: 0.00 AC: 0 AN: 28096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22738

East Asian (EAS) AF: 0.00 AC: 0 AN: 31022

South Asian (SAS) AF: 0.0000137 AC: 1 AN: 72772

European-Finnish (FIN) AF: 0.0000304 AC: 1 AN: 32934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3880

European-Non Finnish (NFE) AF: 0.00000380 AC: 4 AN: 1052272

Other (OTH) AF: 0.00 AC: 0 AN: 55002

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.18

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: rs1288924599; hg19: chr11-67759038;