rs377021545

Positions:

• chr11-67995764-G-A
• chr11-67995764-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000227471.7(UNC93B1):​c.1210C>T​(p.Pro404Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000873 in 1,548,328 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00091 (2 hom.)
• Consequence: UNC93B1 ENST00000227471.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 4.37

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09749627).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC93B1	NM_030930.4	c.1210C>T	p.Pro404Ser	missense_variant	9/11	ENST00000227471.7	NP_112192.2
UNC93B1	XM_011545290.1	c.799C>T	p.Pro267Ser	missense_variant	7/9		XP_011543592.1
UNC93B1	XM_011545291.3	c.655C>T	p.Pro219Ser	missense_variant	6/8		XP_011543593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC93B1	ENST00000227471.7	c.1210C>T	p.Pro404Ser	missense_variant	9/11	1	NM_030930.4	ENSP00000227471	P1
UNC93B1	ENST00000525368.1	n.217C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152004 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000564 AC: 85 AN: 150598 Hom.: 0 AF XY: 0.000593 AC XY: 48 AN XY: 80906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000122

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.000929

GnomAD4 exome AF: 0.000905 AC: 1264 AN: 1396206 Hom.: 2 Cov.: 36 AF XY: 0.000874 AC XY: 602 AN XY: 688704

Gnomad4 AFR exome AF: 0.000254

Gnomad4 AMR exome AF: 0.000476

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000291

Gnomad4 NFE exome AF: 0.00110

Gnomad4 OTH exome AF: 0.000606

GnomAD4 genome AF: 0.000572 AC: 87 AN: 152122 Hom.: 0 Cov.: 29 AF XY: 0.000417 AC XY: 31 AN XY: 74376

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00105

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000813 Hom.: 0

Bravo AF: 0.000601

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00133 AC: 10

ExAC AF: 0.000269 AC: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Herpes simplex encephalitis, susceptibility to, 1 Uncertain:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 02-15-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2022	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 404 of the UNC93B1 protein (p.Pro404Ser). This variant is present in population databases (rs377021545, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with UNC93B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 537922). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.54	N
PrimateAI	Uncertain	0.60	T
REVEL	Benign	0.13
Sift4G	Benign	0.36	T
Polyphen		0.99	D
Vest4		0.45
MVP		0.082
MPC		1.2
ClinPred		0.23	T
GERP RS		5.4
Varity_R		0.10
gMVP		0.49

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: rs377021545; hg19: chr11-67763235; COSMIC: COSV105846693; COSMIC: COSV105846693;