chr11-67991572-C-T

Variant names:

• chr11-67991572-C-T
• rs2375182
• NM_030930.4:c.1768G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000227471.7(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 ENST00000227471.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.38
• Publications: 2 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)

ACMG classification

Our verdict: Benign. The variant received -9 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. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000227471.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	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

Selected	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
	UNC93B1	ENST00000525368.1	TSL:2	n.*246G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 151940 Hom.: 0 Cov.: 33

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: 25 AN: 92742 AF XY: 0.000309

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.: 3 Cov.: 30 AF XY: 0.000322 AC XY: 212 AN XY: 658150

African (AFR) AF: 0.0000370 AC: 1 AN: 27010

American (AMR) AF: 0.000510 AC: 15 AN: 29424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23130

East Asian (EAS) AF: 0.00 AC: 0 AN: 31844

South Asian (SAS) AF: 0.00277 AC: 205 AN: 74000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33140

Middle Eastern (MID) AF: 0.000766 AC: 3 AN: 3918

European-Non Finnish (NFE) AF: 0.0000812 AC: 86 AN: 1058814

Other (OTH) AF: 0.000126 AC: 7 AN: 55562

GnomAD4 genome AF: 0.000178 AC: 27 AN: 152056 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74344

African (AFR) AF: 0.0000722 AC: 3 AN: 41538

American (AMR) AF: 0.000392 AC: 6 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67876

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.0000781 Hom.: 0

ExAC AF: 0.000424 AC: 12

ClinVar

ClinVar submissions as Germline

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	0.34
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.11
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.057	T
Polyphen		1.0	D
Vest4		0.062
MutPred		0.43		Gain of solvent accessibility (P = 0.0037)
MVP		0.043
MPC		0.95
ClinPred		0.13	T
GERP RS		4.6
Varity_R		0.14
gMVP		0.42
Mutation Taster		=92/8	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: rs2375182; hg19: chr11-67759043;