11-118384947-TAAAAAAAAAAAAA-TAAA

Variant names:

• chr11-118384947-TAAAAAAAAAA-T
• rs370025001
• NM_001204077.2:c.2412+14_2412+23delAAAAAAAAAA

Variant summary

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

The ENST00000252108.8(UBE4A):​c.2412+3_2412+12delAAAAAAAAAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000101 in 987,620 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: UBE4A ENST00000252108.8 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.09
• Publications: 0 publications found

Genes affected

UBE4A (HGNC:12499): (ubiquitination factor E4A) This gene encodes a member of the U-box ubiquitin ligase family. The encoded protein is involved in multiubiquitin chain assembly and plays a critical role in chromosome condensation and separation through the polyubiquitination of securin. Autoantibodies against the encoded protein may be markers for scleroderma and Crohn's disease. A pseudogene of this gene is located on the long arm of chromosome 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2011]

UBE4A Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with hypotonia and gross motor and speech delay

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

LOC100131626 (HGNC:):

ACMG classification

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000252108.8. 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
	UBE4A	NM_001204077.2	MANE Select	c.2412+14_2412+23delAAAAAAAAAA		intron	N/A	NP_001191006.1	Q14139-1
	UBE4A	NM_004788.4		c.2433+14_2433+23delAAAAAAAAAA		intron	N/A	NP_004779.2
	LOC100131626	NR_046369.1		n.232-3397_232-3388delTTTTTTTTTT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE4A	ENST00000252108.8	TSL:1 MANE Select	c.2412+3_2412+12delAAAAAAAAAA		splice_region intron	N/A	ENSP00000252108.4	Q14139-1
	UBE4A	ENST00000431736.6	TSL:1	c.2433+3_2433+12delAAAAAAAAAA		splice_region intron	N/A	ENSP00000387362.2	Q14139-2
	UBE4A	ENST00000911347.1		c.2430+3_2430+12delAAAAAAAAAA		splice_region intron	N/A	ENSP00000581406.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000101 AC: 1 AN: 987620 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 503542

⚠️ 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: 22242

American (AMR) AF: 0.00 AC: 0 AN: 28600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18950

East Asian (EAS) AF: 0.00 AC: 0 AN: 34804

South Asian (SAS) AF: 0.00 AC: 0 AN: 63528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3898

European-Non Finnish (NFE) AF: 0.00000136 AC: 1 AN: 738002

Other (OTH) AF: 0.00 AC: 0 AN: 43126

⚠️ 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.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1

Splicing

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

Other links and lift over

dbSNP: rs370025001; hg19: chr11-118255662;