11-67991614-C-T

Variant names:

• chr11-67991614-C-T
• rs1330076422
• NM_030930.4:c.1726G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030930.4(UNC93B1):​c.1726G>A​(p.Ala576Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A576P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UNC93B1 NM_030930.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.535
• 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)
• systemic lupus erythematosus

  Inheritance: SD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08827162).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030930.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC93B1	NM_030930.4	MANE Select	c.1726G>A	p.Ala576Thr	missense	Exon 11 of 11	NP_112192.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC93B1	ENST00000227471.7	TSL:1 MANE Select	c.1726G>A	p.Ala576Thr	missense	Exon 11 of 11	ENSP00000227471.3	Q9H1C4
	UNC93B1	ENST00000864508.1		c.1765G>A	p.Ala589Thr	missense	Exon 11 of 11	ENSP00000534567.1
	UNC93B1	ENST00000864509.1		c.1750G>A	p.Ala584Thr	missense	Exon 11 of 11	ENSP00000534568.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.42e-7 AC: 1 AN: 1347774 Hom.: 0 Cov.: 30 AF XY: 0.00000151 AC XY: 1 AN XY: 664104

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27634

American (AMR) AF: 0.0000332 AC: 1 AN: 30154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23492

East Asian (EAS) AF: 0.00 AC: 0 AN: 33044

South Asian (SAS) AF: 0.00 AC: 0 AN: 74934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3936

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065214

Other (OTH) AF: 0.00 AC: 0 AN: 56170

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Herpes simplex encephalitis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.54
PrimateAI	Uncertain	0.78	T
REVEL	Benign	0.022
Sift4G	Benign	0.47	T
Polyphen		0.029	B
Vest4		0.074
MutPred		0.20		Gain of phosphorylation at A576 (P = 0.0067)
MVP		0.043
MPC		0.51
ClinPred		0.049	T
GERP RS		1.1
Varity_R		0.018
gMVP		0.29
Mutation Taster		=99/1	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: rs1330076422; hg19: chr11-67759085; COSMIC: COSV105054234; COSMIC: COSV105054234;