rs199824078

Positions:

• chr11-67993705-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030930.4(UNC93B1):​c.1453G>A​(p.Val485Met) variant causes a missense change. The variant allele was found at a frequency of 0.00273 in 1,258,826 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (17 hom.)
• Consequence: UNC93B1 NM_030930.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.64

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013433933).
• BP6: Variant 11-67993705-C-T is Benign according to our data. Variant chr11-67993705-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 470491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67993705-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00275 (3043/1106496) while in subpopulation MID AF= 0.0287 (101/3522). AF 95% confidence interval is 0.0241. There are 17 homozygotes in gnomad4_exome. There are 1656 alleles in male gnomad4_exome subpopulation. Median coverage is 15. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC93B1	NM_030930.4	c.1453G>A	p.Val485Met	missense_variant	10/11	ENST00000227471.7
UNC93B1	XM_011545290.1	c.1042G>A	p.Val348Met	missense_variant	8/9
UNC93B1	XM_011545291.3	c.898G>A	p.Val300Met	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC93B1	ENST00000227471.7	c.1453G>A	p.Val485Met	missense_variant	10/11	1	NM_030930.4	P1
UNC93B1	ENST00000525368.1	n.460G>A		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.00260 AC: 396 AN: 152212 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00287

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00422 AC: 600 AN: 142166 Hom.: 4 AF XY: 0.00456 AC XY: 347 AN XY: 76140

Gnomad AFR exome AF: 0.000281

Gnomad AMR exome AF: 0.00533

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00568

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00311

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00275 AC: 3043 AN: 1106496 Hom.: 17 Cov.: 15 AF XY: 0.00297 AC XY: 1656 AN XY: 558282

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00579

Gnomad4 ASJ exome AF: 0.0138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00565

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00209

Gnomad4 OTH exome AF: 0.00473

GnomAD4 genome AF: 0.00261 AC: 397 AN: 152330 Hom.: 1 Cov.: 33 AF XY: 0.00283 AC XY: 211 AN XY: 74496

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00287

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00534 Hom.: 2

Bravo AF: 0.00308

ExAC AF: 0.00150 AC: 145

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Herpes simplex encephalitis, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

UNC93B1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.054	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.70	T
REVEL	Uncertain	0.42
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.51
MVP		0.29
MPC		1.3
ClinPred		0.025	T
GERP RS		5.0
Varity_R		0.26
gMVP		0.87

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

LitVar

Other links and lift over

dbSNP: rs199824078; hg19: chr11-67761176; COSMIC: COSV57098606; COSMIC: COSV57098606;