rs144399212

chr11-67999234-G-A

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.626C>T(p.Pro209Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,613,944 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P209P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (23 hom.)
• Consequence: UNC93B1 NM_030930.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.55

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=0.0077898204).
• BP6: Variant 11-67999234-G-A is Benign according to our data. Variant chr11-67999234-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 470499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-67999234-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00296 (4328/1461572) while in subpopulation MID AF= 0.0373 (215/5768). AF 95% confidence interval is 0.0332. There are 23 homozygotes in gnomad4_exome. There are 2317 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC93B1	NM_030930.4	c.626C>T	p.Pro209Leu	missense_variant	5/11	ENST00000227471.7
UNC93B1	XM_011545290.1	c.215C>T	p.Pro72Leu	missense_variant	3/9
UNC93B1	XM_011545291.3	c.71C>T	p.Pro24Leu	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC93B1	ENST00000227471.7	c.626C>T	p.Pro209Leu	missense_variant	5/11	1	NM_030930.4	P1

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 438 AN: 152254 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00693

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00314

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00388 AC: 965 AN: 248952 Hom.: 5 AF XY: 0.00417 AC XY: 563 AN XY: 135150

Gnomad AFR exome AF: 0.000582

Gnomad AMR exome AF: 0.00553

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00341

Gnomad OTH exome AF: 0.00976

GnomAD4 exome AF: 0.00296 AC: 4328 AN: 1461572 Hom.: 23 Cov.: 32 AF XY: 0.00319 AC XY: 2317 AN XY: 727070

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00601

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00588

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00238

Gnomad4 OTH exome AF: 0.00474

GnomAD4 genome AF: 0.00288 AC: 439 AN: 152372 Hom.: 1 Cov.: 33 AF XY: 0.00310 AC XY: 231 AN XY: 74500

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00692

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00315

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00368 Hom.: 4

Bravo AF: 0.00342

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00299 AC: 25

ExAC AF: 0.00370 AC: 448

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00498

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

Mar 01, 2023

UNC93B1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D;D
MetaRNN	Benign	0.0078	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.19
Sift	Benign	0.11	T;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.98	D;.
Vest4		0.68
MVP		0.068
MPC		1.3
ClinPred		0.026	T
GERP RS		4.2
Varity_R		0.33
gMVP		0.82

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: rs144399212; hg19: chr11-67766704;