rs146593182

Positions:

• chr11-68003029-G-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.385C>A​(p.Leu129Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,611,194 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0029 (23 hom.)
• Consequence: UNC93B1 NM_030930.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.87

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=0.008801967).
• BP6: Variant 11-68003029-G-T is Benign according to our data. Variant chr11-68003029-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 470497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68003029-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00289 (4224/1459078) while in subpopulation MID AF= 0.0374 (215/5746). AF 95% confidence interval is 0.0333. There are 23 homozygotes in gnomad4_exome. There are 2252 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC93B1	NM_030930.4	c.385C>A	p.Leu129Ile	missense_variant	3/11	ENST00000227471.7
UNC93B1	XM_011545290.1	c.-28C>A		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC93B1	ENST00000227471.7	c.385C>A	p.Leu129Ile	missense_variant	3/11	1	NM_030930.4	P1

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 431 AN: 151998 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00688

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00500

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00307

Gnomad OTH AF: 0.00863

GnomAD3 exomes AF: 0.00381 AC: 928 AN: 243836 Hom.: 6 AF XY: 0.00406 AC XY: 538 AN XY: 132650

Gnomad AFR exome AF: 0.000535

Gnomad AMR exome AF: 0.00555

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00334

Gnomad OTH exome AF: 0.00962

GnomAD4 exome AF: 0.00289 AC: 4224 AN: 1459078 Hom.: 23 Cov.: 31 AF XY: 0.00310 AC XY: 2252 AN XY: 725626

Gnomad4 AFR exome AF: 0.00156

Gnomad4 AMR exome AF: 0.00605

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00568

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00231

Gnomad4 OTH exome AF: 0.00463

GnomAD4 genome AF: 0.00284 AC: 432 AN: 152116 Hom.: 1 Cov.: 31 AF XY: 0.00307 AC XY: 228 AN XY: 74350

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00687

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00500

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00307

Gnomad4 OTH AF: 0.00854

Alfa AF: 0.00293 Hom.: 3

Bravo AF: 0.00338

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000232 AC: 1

ESP6500EA AF: 0.00306 AC: 26

ExAC AF: 0.00359 AC: 435

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	UNC93B1: BS2 -

Herpes simplex encephalitis, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Benign	0.0088	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.92	N;N
REVEL	Benign	0.12
Sift	Benign	0.27	T;T
Sift4G	Benign	0.16	T;D
Polyphen		1.0	D;.
Vest4		0.60
MVP		0.068
MPC		1.0
ClinPred		0.023	T
GERP RS		4.2
Varity_R		0.24
gMVP		0.39

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: rs146593182; hg19: chr11-67770499;