11-118384947-TAAA-T

Variant names:

• chr11-118384947-TAAA-T
• rs370025001
• NM_001204077.2:c.2412+21_2412+23delAAA

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+5delAAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0565 in 999,732 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 29)
  • Exomes 𝑓: 0.061 (0 hom.)
• Consequence: UBE4A ENST00000252108.8 splice_region, 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the AMR (0.0702) population. However there is too low homozygotes in high coverage region: (expected more than 799, got 0).

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+21_2412+23delAAA		intron	N/A	NP_001191006.1	Q14139-1
	UBE4A	NM_004788.4		c.2433+21_2433+23delAAA		intron	N/A	NP_004779.2
	LOC100131626	NR_046369.1		n.232-3390_232-3388delTTT		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+5delAAA		splice_region intron	N/A	ENSP00000252108.4	Q14139-1
	UBE4A	ENST00000431736.6	TSL:1	c.2433+3_2433+5delAAA		splice_region intron	N/A	ENSP00000387362.2	Q14139-2
	UBE4A	ENST00000911347.1		c.2430+3_2430+5delAAA		splice_region intron	N/A	ENSP00000581406.1

Frequencies

GnomAD3 genomes AF: 0.000340 AC: 27 AN: 79454 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000435

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.116 AC: 9713 AN: 83660 AF XY: 0.116

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.110

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.0614 AC: 56500 AN: 920288 Hom.: 0 AF XY: 0.0619 AC XY: 28878 AN XY: 466892

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

African (AFR) AF: 0.0713 AC: 1471 AN: 20620

American (AMR) AF: 0.0730 AC: 1794 AN: 24576

Ashkenazi Jewish (ASJ) AF: 0.0725 AC: 1249 AN: 17232

East Asian (EAS) AF: 0.0717 AC: 2194 AN: 30610

South Asian (SAS) AF: 0.0598 AC: 3444 AN: 57600

European-Finnish (FIN) AF: 0.0741 AC: 2285 AN: 30822

Middle Eastern (MID) AF: 0.0593 AC: 218 AN: 3676

European-Non Finnish (NFE) AF: 0.0592 AC: 41177 AN: 695360

Other (OTH) AF: 0.0670 AC: 2668 AN: 39792

⚠️ 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: 0.000340 AC: 27 AN: 79444 Hom.: 0 Cov.: 29 AF XY: 0.000424 AC XY: 16 AN XY: 37742

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

African (AFR) AF: 0.000228 AC: 5 AN: 21894

American (AMR) AF: 0.000435 AC: 3 AN: 6898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1996

East Asian (EAS) AF: 0.00 AC: 0 AN: 2934

South Asian (SAS) AF: 0.00 AC: 0 AN: 2550

European-Finnish (FIN) AF: 0.00192 AC: 8 AN: 4176

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

European-Non Finnish (NFE) AF: 0.000294 AC: 11 AN: 37398

Other (OTH) AF: 0.00 AC: 0 AN: 1030

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=90/10	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs370025001;

hg19: chr11-118255662;