chr11-67991563-C-G

Variant names:

• chr11-67991563-C-G
• rs964738111
• NM_030930.4:c.1777G>C

Variant summary

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

The NM_030930.4(UNC93B1):​c.1777G>C​(p.Gly593Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 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. G593E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000098 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UNC93B1 NM_030930.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07540661).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC93B1	NM_030930.4	c.1777G>C	p.Gly593Arg	missense_variant	Exon 11 of 11	ENST00000227471.7	NP_112192.2
UNC93B1	XM_011545290.1	c.1366G>C	p.Gly456Arg	missense_variant	Exon 9 of 9		XP_011543592.1
UNC93B1	XM_011545291.3	c.1222G>C	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	c.1777G>C	p.Gly593Arg	missense_variant	Exon 11 of 11	1	NM_030930.4	ENSP00000227471.3

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 45 AN: 149172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

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: 0.00

Gnomad OTH AF: 0.000968

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000983 AC: 13 AN: 1321816 Hom.: 0 Cov.: 30 AF XY: 0.00000924 AC XY: 6 AN XY: 649122

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

African (AFR) AF: 0.000191 AC: 5 AN: 26124

American (AMR) AF: 0.00 AC: 0 AN: 27744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22566

East Asian (EAS) AF: 0.0000324 AC: 1 AN: 30906

South Asian (SAS) AF: 0.0000138 AC: 1 AN: 72432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3868

European-Non Finnish (NFE) AF: 0.00000381 AC: 4 AN: 1050488

Other (OTH) AF: 0.0000365 AC: 2 AN: 54828

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000301 AC: 45 AN: 149262 Hom.: 0 Cov.: 33 AF XY: 0.000274 AC XY: 20 AN XY: 73048

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

African (AFR) AF: 0.00105 AC: 41 AN: 39142

American (AMR) AF: 0.000132 AC: 2 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67596

Other (OTH) AF: 0.000958 AC: 2 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000389 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.0
PrimateAI	Uncertain	0.78	T
REVEL	Benign	0.063
Sift4G	Pathogenic	0.0	D
Polyphen		0.50	P
Vest4		0.072
MutPred		0.44		Gain of solvent accessibility (P = 0.1319);
MVP		0.043
MPC		1.4
ClinPred		0.85	D
GERP RS		3.7
Varity_R		0.13
gMVP		0.15
Mutation Taster		=97/3	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: rs964738111; hg19: chr11-67759034;