11-67996789-G-T

Variant names:

• chr11-67996789-G-T
• rs144979304
• NM_030930.4:c.907-5C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_030930.4(UNC93B1):​c.907-5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,387,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: UNC93B1 NM_030930.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.498
• Publications: 0 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC93B1	NM_030930.4	c.907-5C>A		splice_region_variant, intron_variant	Intron 7 of 10	ENST00000227471.7	NP_112192.2
UNC93B1	XM_011545290.1	c.496-5C>A		splice_region_variant, intron_variant	Intron 5 of 8		XP_011543592.1
UNC93B1	XM_011545291.3	c.352-5C>A		splice_region_variant, intron_variant	Intron 4 of 7		XP_011543593.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC93B1	ENST00000227471.7	c.907-5C>A		splice_region_variant, intron_variant	Intron 7 of 10	1	NM_030930.4	ENSP00000227471.3
UNC93B1	ENST00000533424.6	n.1401-5C>A		splice_region_variant, intron_variant	Intron 6 of 6	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1387640 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 681592

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31360

American (AMR) AF: 0.00 AC: 0 AN: 36794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24810

East Asian (EAS) AF: 0.00 AC: 0 AN: 35594

South Asian (SAS) AF: 0.00 AC: 0 AN: 78468

European-Finnish (FIN) AF: 0.0000202 AC: 1 AN: 49484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4384

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1069728

Other (OTH) AF: 0.00 AC: 0 AN: 57018

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.5
DANN	Benign	0.74
PhyloP100		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: -2
DS_AL_spliceai		0.34		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144979304; hg19: chr11-67764260;