rs2375182

chr11-67991572-C-Achr11-67991572-C-Gchr11-67991572-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_030930.4(UNC93B1):c.1768G>T(p.Gly590Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,488,914 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G590R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0089 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (27 hom.)
• Consequence: UNC93B1 NM_030930.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.38

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035933256).
• BP6: Variant 11-67991572-C-A is Benign according to our data. Variant chr11-67991572-C-A is described in ClinVar as [Benign]. Clinvar id is 470495.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00888 (1351/152056) while in subpopulation AFR AF= 0.0232 (962/41536). AF 95% confidence interval is 0.0219. There are 12 homozygotes in gnomad4. There are 652 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC93B1	NM_030930.4	c.1768G>T	p.Gly590Trp	missense_variant	11/11	ENST00000227471.7
UNC93B1	XM_011545290.1	c.1357G>T	p.Gly453Trp	missense_variant	9/9
UNC93B1	XM_011545291.3	c.1213G>T	p.Gly405Trp	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC93B1	ENST00000227471.7	c.1768G>T	p.Gly590Trp	missense_variant	11/11	1	NM_030930.4	P1

Frequencies

GnomAD3 genomes AF: 0.00887 AC: 1347 AN: 151940 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00426

Gnomad OTH AF: 0.00767

GnomAD3 exomes AF: 0.00290 AC: 269 AN: 92742 Hom.: 2 AF XY: 0.00255 AC XY: 132 AN XY: 51842

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00266

Gnomad EAS exome AF: 0.000505

Gnomad SAS exome AF: 0.000176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00381

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00399 AC: 5336 AN: 1336858 Hom.: 27 Cov.: 30 AF XY: 0.00389 AC XY: 2557 AN XY: 658162

Gnomad4 AFR exome AF: 0.0265

Gnomad4 AMR exome AF: 0.00370

Gnomad4 ASJ exome AF: 0.00316

Gnomad4 EAS exome AF: 0.000345

Gnomad4 SAS exome AF: 0.000230

Gnomad4 FIN exome AF: 0.000332

Gnomad4 NFE exome AF: 0.00382

Gnomad4 OTH exome AF: 0.00625

GnomAD4 genome AF: 0.00888 AC: 1351 AN: 152056 Hom.: 12 Cov.: 33 AF XY: 0.00877 AC XY: 652 AN XY: 74344

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00426

Gnomad4 OTH AF: 0.00759

Alfa AF: 0.00121 Hom.: 0

Bravo AF: 0.0102

ExAC AF: 0.00124 AC: 35

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Herpes simplex encephalitis, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.054
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.98	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.47		Loss of relative solvent accessibility (P = 0.0186);
MVP		0.043
MPC		1.3
ClinPred		0.027	T
GERP RS		4.6
Varity_R		0.18
gMVP		0.38

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: rs2375182; hg19: chr11-67759043; COSMIC: COSV57097970; COSMIC: COSV57097970;