NM_001204077.2:c.2412+22_2412+23dupAA

Variant names:

• chr11-118384947-T-TAA
• rs370025001
• NM_001204077.2:c.2412+22_2412+23dupAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001204077.2(UBE4A):​c.2412+22_2412+23dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000885 in 1,066,192 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00088 (1 hom.)
• Consequence: UBE4A NM_001204077.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.09
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000994 (79/79466) while in subpopulation AFR AF = 0.00228 (50/21894). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204077.2. 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+22_2412+23dupAA		intron	N/A	NP_001191006.1	Q14139-1
	UBE4A	NM_004788.4		c.2433+22_2433+23dupAA		intron	N/A	NP_004779.2
	LOC100131626	NR_046369.1		n.232-3389_232-3388dupTT		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+2_2412+3insAA		splice_region intron	N/A	ENSP00000252108.4	Q14139-1
	UBE4A	ENST00000431736.6	TSL:1	c.2433+2_2433+3insAA		splice_region intron	N/A	ENSP00000387362.2	Q14139-2
	UBE4A	ENST00000911347.1		c.2430+2_2430+3insAA		splice_region intron	N/A	ENSP00000581406.1

Frequencies

GnomAD3 genomes AF: 0.000994 AC: 79 AN: 79476 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00130

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000339

Gnomad SAS AF: 0.00155

Gnomad FIN AF: 0.000477

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000347

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000877 AC: 865 AN: 986726 Hom.: 1 Cov.: 0 AF XY: 0.000889 AC XY: 447 AN XY: 503060

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

African (AFR) AF: 0.00130 AC: 29 AN: 22224

American (AMR) AF: 0.000735 AC: 21 AN: 28560

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 21 AN: 18938

East Asian (EAS) AF: 0.000575 AC: 20 AN: 34782

South Asian (SAS) AF: 0.00151 AC: 96 AN: 63420

European-Finnish (FIN) AF: 0.000464 AC: 16 AN: 34450

Middle Eastern (MID) AF: 0.00103 AC: 4 AN: 3894

European-Non Finnish (NFE) AF: 0.000845 AC: 623 AN: 737362

Other (OTH) AF: 0.000812 AC: 35 AN: 43096

⚠️ 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 AF: 0.000994 AC: 79 AN: 79466 Hom.: 0 Cov.: 29 AF XY: 0.00101 AC XY: 38 AN XY: 37768

African (AFR) AF: 0.00228 AC: 50 AN: 21894

American (AMR) AF: 0.00130 AC: 9 AN: 6898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2000

East Asian (EAS) AF: 0.000341 AC: 1 AN: 2934

South Asian (SAS) AF: 0.00157 AC: 4 AN: 2548

European-Finnish (FIN) AF: 0.000477 AC: 2 AN: 4190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 116

European-Non Finnish (NFE) AF: 0.000348 AC: 13 AN: 37408

Other (OTH) AF: 0.00 AC: 0 AN: 1028

Alfa AF: 0.00 Hom.: 14

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=93/7	polymorphism

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;