Genetic Variant NM_030930.4:c.1720G>A (chr11-67991620-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_030930.4(UNC93B1):c.1720G>A(p.Glu574Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,349,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E574Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

UNC93B1
NM_030930.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.567

Publications

0 publications found

Variant links:

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)

UNC93B1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08099714).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
UNC93B1	NM_030930.4 link	c.1720G>A	p.Glu574Lys	missense_variant	Exon 11 of 11	ENST00000227471.7	NP_112192.2
UNC93B1	XM_011545290.1 link	c.1309G>A	p.Glu437Lys	missense_variant	Exon 9 of 9		XP_011543592.1
UNC93B1	XM_011545291.3 link	c.1165G>A	p.Glu389Lys	missense_variant	Exon 8 of 8		XP_011543593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC93B1	ENST00000227471.7 link	c.1720G>A	p.Glu574Lys	missense_variant	Exon 11 of 11	1	NM_030930.4	ENSP00000227471.3
UNC93B1	ENST00000525368.1 link	n.*198G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000148

AC:

AN:

1349994

Hom.:

Cov.:

AF XY:

0.00000301

AC XY:

AN XY:

665324

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27764

American (AMR)

AF:

0.00

AC:

AN:

30320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23512

East Asian (EAS)

AF:

0.00

AC:

AN:

33284

South Asian (SAS)

AF:

0.00

AC:

AN:

75220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33200

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3940

European-Non Finnish (NFE)

AF:

0.00000188

AC:

AN:

1066466

Other (OTH)

AF:

0.00

AC:

AN:

56288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.14

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.66

M_CAP

Benign

0.047

MetaRNN

Benign

0.081

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.9

PhyloP100

0.57

PrimateAI

Pathogenic

0.82

REVEL

Benign

0.019

Sift4G

Benign

0.76

Polyphen

0.0010

Vest4

0.080

MutPred

0.22

Gain of methylation at E574 (P = 0.003);

MVP

0.043

MPC

0.47

ClinPred

0.081

GERP RS

1.6

Varity_R

0.078

gMVP

0.29

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over