11-67991563-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_030930.4(UNC93B1):c.1777G>A(p.Gly593Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,472,490 control chromosomes in the GnomAD database, including 1 homozygotes. 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. G593E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

UNC93B1
NM_030930.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.03

Publications

2 publications found

Variant links:

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)

UNC93B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04903993).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000206 (31/150422) while in subpopulation AMR AF = 0.000854 (13/15218). AF 95% confidence interval is 0.000505. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC93B1	NM_030930.4 link	c.1777G>A	p.Gly593Arg	missense_variant	Exon 11 of 11	ENST00000227471.7	NP_112192.2	Q9H1C4
UNC93B1	XM_011545290.1 link	c.1366G>A	p.Gly456Arg	missense_variant	Exon 9 of 9		XP_011543592.1
UNC93B1	XM_011545291.3 link	c.1222G>A	p.Gly408Arg	missense_variant	Exon 8 of 8		XP_011543593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC93B1	ENST00000227471.7 link	c.1777G>A	p.Gly593Arg	missense_variant	Exon 11 of 11	1	NM_030930.4	ENSP00000227471.3		Q9H1C4

Frequencies

GnomAD3 genomes

AF:

0.000206

AC:

AN:

150320

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000499

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000855

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000148

Gnomad OTH

AF:

0.00289

GnomAD2 exomes

AF:

0.000236

AC:

AN:

84622

AF XY:

0.000190

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000923

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000144

AC:

191

AN:

1322068

Hom.:

Cov.:

AF XY:

0.000126

AC XY:

AN XY:

649234

show subpopulations

African (AFR)

AF:

0.0000381

AC:

AN:

26264

American (AMR)

AF:

0.000793

AC:

AN:

27754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22566

East Asian (EAS)

AF:

0.00

AC:

AN:

30934

South Asian (SAS)

AF:

0.00

AC:

AN:

72432

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32862

Middle Eastern (MID)

AF:

0.00181

AC:

AN:

3870

European-Non Finnish (NFE)

AF:

0.000121

AC:

127

AN:

1050546

Other (OTH)

AF:

0.000620

AC:

AN:

54840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000206

AC:

AN:

150422

Hom.:

Cov.:

AF XY:

0.000231

AC XY:

AN XY:

73586

show subpopulations

African (AFR)

AF:

0.0000498

AC:

AN:

40154

American (AMR)

AF:

0.000854

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000148

AC:

AN:

67694

Other (OTH)

AF:

0.00286

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000389

Hom.:

Bravo

AF:

0.000419

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Herpes simplex encephalitis, susceptibility to, 1

Uncertain:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 593 of the UNC93B1 protein (p.Gly593Arg). This variant is present in population databases (no rsID available, 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: 834530). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Not Available". The arginine 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

0.23

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.83

M_CAP

Benign

0.076

MetaRNN

Benign

0.049

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.1

PhyloP100

1.0

PrimateAI

Uncertain

0.78

REVEL

Benign

0.084

Sift4G

Pathogenic

0.0

Polyphen

0.69

Vest4

0.072

MutPred

0.44

Gain of solvent accessibility (P = 0.1319);

MVP

0.043

MPC

1.4

ClinPred

0.065

GERP RS

3.7

Varity_R

0.13

gMVP

0.15

Mutation Taster

=97/3

polymorphism

(source)

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

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11-67991563-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over