rs199824078

Variant names:

• chr11-67993705-C-T
• rs199824078
• NM_030930.4:c.1453G>A

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 4.64
• 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 470491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00261 (397/152330) while in subpopulation AMR AF = 0.00588 (90/15308). AF 95% confidence interval is 0.0049. There are 1 homozygotes in GnomAd4. There are 211 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC93B1	NM_030930.4	MANE Select	c.1453G>A	p.Val485Met	missense	Exon 10 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.1453G>A	p.Val485Met	missense	Exon 10 of 11	ENSP00000227471.3
	UNC93B1	ENST00000525368.1	TSL:2	n.460G>A		non_coding_transcript_exon	Exon 2 of 3

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

GnomAD2 exomes AF: 0.00422 AC: 600 AN: 142166 AF XY: 0.00456

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 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

African (AFR) AF: 0.00146 AC: 38 AN: 26110

American (AMR) AF: 0.00579 AC: 205 AN: 35422

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 325 AN: 23510

East Asian (EAS) AF: 0.00 AC: 0 AN: 34498

South Asian (SAS) AF: 0.00565 AC: 418 AN: 73938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34948

Middle Eastern (MID) AF: 0.0287 AC: 101 AN: 3522

European-Non Finnish (NFE) AF: 0.00209 AC: 1726 AN: 825904

Other (OTH) AF: 0.00473 AC: 230 AN: 48644

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

African (AFR) AF: 0.000529 AC: 22 AN: 41574

American (AMR) AF: 0.00588 AC: 90 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00287 AC: 195 AN: 68018

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00534 Hom.: 2

Bravo AF: 0.00308

ExAC AF: 0.00150 AC: 145

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Herpes simplex encephalitis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.6
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
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: rs199824078; hg19: chr11-67761176; COSMIC: COSV57098606; COSMIC: COSV57098606;