chr11-67995764-G-A

Variant names:

• chr11-67995764-G-A
• rs377021545
• NM_030930.4:c.1210C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_030930.4(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 NM_030930.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 4.37
• Publications: 2 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)
• systemic lupus erythematosus

  Inheritance: SD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09749627).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000572 (87/152122) while in subpopulation NFE AF = 0.00105 (71/67942). AF 95% confidence interval is 0.000849. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 SD,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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC93B1	NM_030930.4	MANE Select	c.1210C>T	p.Pro404Ser	missense	Exon 9 of 11	NP_112192.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC93B1	ENST00000227471.7	TSL:1 MANE Select	c.1210C>T	p.Pro404Ser	missense	Exon 9 of 11	ENSP00000227471.3	Q9H1C4
	UNC93B1	ENST00000864508.1		c.1249C>T	p.Pro417Ser	missense	Exon 9 of 11	ENSP00000534567.1
	UNC93B1	ENST00000864509.1		c.1234C>T	p.Pro412Ser	missense	Exon 9 of 11	ENSP00000534568.1

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

GnomAD2 exomes AF: 0.000564 AC: 85 AN: 150598 AF XY: 0.000593

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 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

African (AFR) AF: 0.000254 AC: 8 AN: 31530

American (AMR) AF: 0.000476 AC: 17 AN: 35716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 35746

South Asian (SAS) AF: 0.00 AC: 0 AN: 79156

European-Finnish (FIN) AF: 0.000291 AC: 14 AN: 48176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4062

European-Non Finnish (NFE) AF: 0.00110 AC: 1190 AN: 1078868

Other (OTH) AF: 0.000606 AC: 35 AN: 57796

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

African (AFR) AF: 0.000120 AC: 5 AN: 41502

American (AMR) AF: 0.000457 AC: 7 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00105 AC: 71 AN: 67942

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Herpes simplex encephalitis, susceptibility to, 1 (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.4
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
Mutation Taster		=81/19	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: rs377021545; hg19: chr11-67763235; COSMIC: COSV105846693; COSMIC: COSV105846693;