11-67991572-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_030930.4(UNC93B1):c.1768G>A(p.Gly590Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,488,898 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G590W) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 3 hom. )

Consequence

UNC93B1
NM_030930.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.38

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)
systemic lupus erythematosus
Inheritance: SD Classification: MODERATE Submitted by: ClinGen

UNC93B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013512254).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000178 (27/152056) while in subpopulation SAS AF = 0.00166 (8/4818). AF 95% confidence interval is 0.000826. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 SD,AR gene

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.1768G>A	p.Gly590Arg	missense	Exon 11 of 11	NP_112192.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
UNC93B1	ENST00000227471.7	TSL:1 MANE Select	c.1768G>A	p.Gly590Arg	missense	Exon 11 of 11	ENSP00000227471.3	Q9H1C4
UNC93B1	ENST00000864508.1		c.1807G>A	p.Gly603Arg	missense	Exon 11 of 11	ENSP00000534567.1
UNC93B1	ENST00000864509.1		c.1792G>A	p.Gly598Arg	missense	Exon 11 of 11	ENSP00000534568.1

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

151940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000270

AC:

AN:

92742

AF XY:

0.000309

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000169

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000272

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000237

AC:

317

AN:

1336842

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

212

AN XY:

658150

show subpopulations

African (AFR)

AF:

0.0000370

AC:

AN:

27010

American (AMR)

AF:

0.000510

AC:

AN:

29424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23130

East Asian (EAS)

AF:

0.00

AC:

AN:

31844

South Asian (SAS)

AF:

0.00277

AC:

205

AN:

74000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33140

Middle Eastern (MID)

AF:

0.000766

AC:

AN:

3918

European-Non Finnish (NFE)

AF:

0.0000812

AC:

AN:

1058814

Other (OTH)

AF:

0.000126

AC:

AN:

55562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000178

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41538

American (AMR)

AF:

0.000392

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00166

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

67876

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000781

Hom.:

ExAC

AF:

0.000424

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Herpes simplex encephalitis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.80

M_CAP

Benign

0.048

MetaRNN

Benign

0.014

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

3.4

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.66

REVEL

Benign

0.11

Sift

Uncertain

0.023

Sift4G

Uncertain

0.057

Polyphen

1.0

Vest4

0.062

MutPred

0.43

Gain of solvent accessibility (P = 0.0037)

MVP

0.043

MPC

0.95

ClinPred

0.13

GERP RS

4.6

Varity_R

0.14

gMVP

0.42

Mutation Taster

=92/8

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over