rs2375179

chr11-67991679-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_030930.4(UNC93B1):c.1661G>A(p.Gly554Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000751 in 1,531,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 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. G554S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: UNC93B1 NM_030930.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.929

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01652494).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC93B1	NM_030930.4	c.1661G>A	p.Gly554Asp	missense_variant	11/11	ENST00000227471.7
UNC93B1	XM_011545290.1	c.1250G>A	p.Gly417Asp	missense_variant	9/9
UNC93B1	XM_011545291.3	c.1106G>A	p.Gly369Asp	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC93B1	ENST00000227471.7	c.1661G>A	p.Gly554Asp	missense_variant	11/11	1	NM_030930.4	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152100 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000188 AC: 24 AN: 127904 Hom.: 0 AF XY: 0.000186 AC XY: 13 AN XY: 69914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000703

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000451

Gnomad FIN exome AF: 0.000379

Gnomad NFE exome AF: 0.0000208

Gnomad OTH exome AF: 0.000759

GnomAD4 exome AF: 0.0000711 AC: 98 AN: 1379180 Hom.: 0 Cov.: 30 AF XY: 0.0000647 AC XY: 44 AN XY: 680554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000674

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000506

Gnomad4 FIN exome AF: 0.000445

Gnomad4 NFE exome AF: 0.0000371

Gnomad4 OTH exome AF: 0.000243

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74402

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.0000200 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Herpes simplex encephalitis, susceptibility to, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2022

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 554 of the UNC93B1 protein (p.Gly554Asp). This variant is present in population databases (rs2375179, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with UNC93B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 470493). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	7.3
Dann	Benign	0.93
DEOGEN2	Benign	0.070	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.70	T
REVEL	Benign	0.019
Sift4G	Benign	0.33	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.21		Gain of helix (P = 0.0164);
MVP		0.043
MPC		0.55
ClinPred		0.0077	T
GERP RS		-5.0
Varity_R		0.044
gMVP		0.25

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: rs2375179; hg19: chr11-67759150;