11-67997690-GA-GAA

Position:

• chr11-67997690-GA-GAA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 10P and 2B. PVS1 PM2 BP6_Moderate

The NM_030930.4(UNC93B1):​c.890dupT​(p.Leu298fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: UNC93B1 NM_030930.4 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.30

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 11-67997690-G-GA is Benign according to our data. Variant chr11-67997690-G-GA is described in ClinVar as [Benign]. Clinvar id is 403594.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC93B1	NM_030930.4	c.890dupT	p.Leu298fs	frameshift_variant	7/11	ENST00000227471.7	NP_112192.2
UNC93B1	XM_011545290.1	c.479dupT	p.Leu161fs	frameshift_variant	5/9		XP_011543592.1
UNC93B1	XM_011545291.3	c.335dupT	p.Leu113fs	frameshift_variant	4/8		XP_011543593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC93B1	ENST00000227471.7	c.890dupT	p.Leu298fs	frameshift_variant	7/11	1	NM_030930.4	ENSP00000227471.3
UNC93B1	ENST00000533424.6	n.1384dupT		non_coding_transcript_exon_variant	6/7	5
UNC93B1	ENST00000622364.4	n.888dupT		non_coding_transcript_exon_variant	7/7	2
UNC93B1	ENST00000531152.3	n.*28dupT		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 12192/12202=0.99% -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060499915; hg19: chr11-67765161;