chr11-67991598-C-G

Variant names:

• chr11-67991598-C-G
• rs754871549
• NM_030930.4:c.1742G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030930.4(UNC93B1):​c.1742G>C​(p.Arg581Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000297 in 1,344,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R581L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: UNC93B1 NM_030930.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.57
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23689857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC93B1	NM_030930.4	c.1742G>C	p.Arg581Pro	missense_variant	Exon 11 of 11	ENST00000227471.7	NP_112192.2
UNC93B1	XM_011545290.1	c.1331G>C	p.Arg444Pro	missense_variant	Exon 9 of 9		XP_011543592.1
UNC93B1	XM_011545291.3	c.1187G>C	p.Arg396Pro	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	c.1742G>C	p.Arg581Pro	missense_variant	Exon 11 of 11	1	NM_030930.4	ENSP00000227471.3
UNC93B1	ENST00000525368.1	n.*220G>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000297 AC: 4 AN: 1344968 Hom.: 0 Cov.: 30 AF XY: 0.00000604 AC XY: 4 AN XY: 662476

African (AFR) AF: 0.00 AC: 0 AN: 27430

American (AMR) AF: 0.00 AC: 0 AN: 30112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23392

East Asian (EAS) AF: 0.00 AC: 0 AN: 32746

South Asian (SAS) AF: 0.00 AC: 0 AN: 74776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3936

European-Non Finnish (NFE) AF: 0.00000376 AC: 4 AN: 1063362

Other (OTH) AF: 0.00 AC: 0 AN: 56016

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.6
PrimateAI	Pathogenic	0.88	D
REVEL	Benign	0.074
Sift4G	Uncertain	0.013	D
Polyphen		0.61	P
Vest4		0.30
MutPred		0.27		Gain of glycosylation at R581 (P = 0.0585);
MVP		0.043
MPC		1.1
ClinPred		0.69	D
GERP RS		3.6
Varity_R		0.15
gMVP		0.46
Mutation Taster		=85/15	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: rs754871549; hg19: chr11-67759069;