chr11-118384947-TAAAAAAAAAAA-T

Variant names:

• chr11-118384947-TAAAAAAAAAAA-T
• rs370025001
• NM_001204077.2:c.2412+13_2412+23delAAAAAAAAAAA

Variant summary

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

The ENST00000252108.8(UBE4A):​c.2412+3_2412+13delAAAAAAAAAAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,067,126 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00015 (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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0024 (191/79504) while in subpopulation AMR AF = 0.00739 (51/6898). AF 95% confidence interval is 0.00578. There are 0 homozygotes in GnomAd4. There are 76 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: 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+13_2412+23delAAAAAAAAAAA		intron	N/A	NP_001191006.1	Q14139-1
	UBE4A	NM_004788.4		c.2433+13_2433+23delAAAAAAAAAAA		intron	N/A	NP_004779.2
	LOC100131626	NR_046369.1		n.232-3398_232-3388delTTTTTTTTTTT		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+13delAAAAAAAAAAA		splice_region intron	N/A	ENSP00000252108.4	Q14139-1
	UBE4A	ENST00000431736.6	TSL:1	c.2433+3_2433+13delAAAAAAAAAAA		splice_region intron	N/A	ENSP00000387362.2	Q14139-2
	UBE4A	ENST00000911347.1		c.2430+3_2430+13delAAAAAAAAAAA		splice_region intron	N/A	ENSP00000581406.1

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 191 AN: 79514 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00622

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000267

Gnomad OTH AF: 0.00295

GnomAD4 exome AF: 0.000146 AC: 144 AN: 987622 Hom.: 0 AF XY: 0.000113 AC XY: 57 AN XY: 503546

African (AFR) AF: 0.00481 AC: 107 AN: 22242

American (AMR) AF: 0.000734 AC: 21 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: 34472

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 738002

Other (OTH) AF: 0.000371 AC: 16 AN: 43126

GnomAD4 genome AF: 0.00240 AC: 191 AN: 79504 Hom.: 0 Cov.: 29 AF XY: 0.00201 AC XY: 76 AN XY: 37782

African (AFR) AF: 0.00621 AC: 136 AN: 21902

American (AMR) AF: 0.00739 AC: 51 AN: 6898

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

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4192

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

European-Non Finnish (NFE) AF: 0.0000267 AC: 1 AN: 37428

Other (OTH) AF: 0.00291 AC: 3 AN: 1032

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

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;