11-67991607-A-T

Variant names:

• chr11-67991607-A-T
• rs1402199169
• NM_030930.4:c.1733T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_030930.4(UNC93B1):​c.1733T>A​(p.Leu578His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 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. L578R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000045 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UNC93B1 NM_030930.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.41
• Publications: 0 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)
• systemic lupus erythematosus

  Inheritance: SD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06846395).

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.1733T>A	p.Leu578His	missense	Exon 11 of 11	NP_112192.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC93B1	ENST00000227471.7	TSL:1 MANE Select	c.1733T>A	p.Leu578His	missense	Exon 11 of 11	ENSP00000227471.3	Q9H1C4
	UNC93B1	ENST00000864508.1		c.1772T>A	p.Leu591His	missense	Exon 11 of 11	ENSP00000534567.1
	UNC93B1	ENST00000864509.1		c.1757T>A	p.Leu586His	missense	Exon 11 of 11	ENSP00000534568.1

Frequencies

GnomAD3 genomes AF: 0.000261 AC: 39 AN: 149502 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000890

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000296

Gnomad OTH AF: 0.000962

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000446 AC: 6 AN: 1344602 Hom.: 0 Cov.: 30 AF XY: 0.00000453 AC XY: 3 AN XY: 662506

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000147 AC: 4 AN: 27186

American (AMR) AF: 0.00 AC: 0 AN: 29716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23406

East Asian (EAS) AF: 0.00 AC: 0 AN: 32728

South Asian (SAS) AF: 0.00 AC: 0 AN: 74758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3924

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1063736

Other (OTH) AF: 0.00 AC: 0 AN: 55958

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000267 AC: 40 AN: 149592 Hom.: 0 Cov.: 33 AF XY: 0.000260 AC XY: 19 AN XY: 73202

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000913 AC: 36 AN: 39442

American (AMR) AF: 0.00 AC: 0 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67628

Other (OTH) AF: 0.000952 AC: 2 AN: 2100

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00325 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.12
DANN	Benign	0.58
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L
PhyloP100		-1.4
PrimateAI	Uncertain	0.77	T
REVEL	Benign	0.0090
Sift4G	Benign	0.16	T
Polyphen		0.14	B
Vest4		0.19
MutPred		0.21		Gain of glycosylation at P573 (P = 0.2199)
MVP		0.043
MPC		0.82
ClinPred		0.042	T
GERP RS		-2.6
Varity_R		0.036
gMVP		0.29
Mutation Taster		=98/2	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: rs1402199169; hg19: chr11-67759078;