11-118384947-TAAAAAAAAAAAAA-TAAAAAAAA

Variant names:

• chr11-118384947-TAAAAA-T
• rs370025001
• NM_001204077.2:c.2412+19_2412+23delAAAAA

Variant summary

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

The NM_001204077.2(UBE4A):​c.2412+19_2412+23delAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,056,924 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: 𝑓 0.000038 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0045 (0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the AFR (0.00552) population. However there is too low homozygotes in high coverage region: (expected more than 4, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE4A	NM_001204077.2	c.2412+19_2412+23delAAAAA		intron_variant	Intron 15 of 19	ENST00000252108.8	NP_001191006.1
UBE4A	NM_004788.4	c.2433+19_2433+23delAAAAA		intron_variant	Intron 15 of 19		NP_004779.2
LOC100131626	NR_046369.1	n.232-3392_232-3388delTTTTT		intron_variant	Intron 3 of 3
LOC100131626	NR_046370.1	n.232-3445_232-3441delTTTTT		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE4A	ENST00000252108.8	c.2412+3_2412+7delAAAAA		splice_region_variant, intron_variant	Intron 15 of 19	1	NM_001204077.2	ENSP00000252108.4
UBE4A	ENST00000431736.6	c.2433+3_2433+7delAAAAA		splice_region_variant, intron_variant	Intron 15 of 19	1		ENSP00000387362.2
UBE4A	ENST00000545354.1	c.828+3_828+7delAAAAA		splice_region_variant, intron_variant	Intron 6 of 10	2		ENSP00000438918.1

Frequencies

GnomAD3 genomes AF: 0.0000377 AC: 3 AN: 79508 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000478

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000267

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00485 AC: 406 AN: 83660 AF XY: 0.00482

Gnomad AFR exome AF: 0.00457

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.00726

Gnomad EAS exome AF: 0.00552

Gnomad FIN exome AF: 0.00596

Gnomad NFE exome AF: 0.00430

Gnomad OTH exome AF: 0.00513

GnomAD4 exome AF: 0.00449 AC: 4390 AN: 977416 Hom.: 0 AF XY: 0.00448 AC XY: 2233 AN XY: 498186

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

African (AFR) AF: 0.00638 AC: 140 AN: 21928

American (AMR) AF: 0.00450 AC: 127 AN: 28216

Ashkenazi Jewish (ASJ) AF: 0.00590 AC: 110 AN: 18654

East Asian (EAS) AF: 0.00380 AC: 130 AN: 34246

South Asian (SAS) AF: 0.00379 AC: 238 AN: 62730

European-Finnish (FIN) AF: 0.00430 AC: 146 AN: 33980

Middle Eastern (MID) AF: 0.00518 AC: 20 AN: 3858

European-Non Finnish (NFE) AF: 0.00451 AC: 3297 AN: 731166

Other (OTH) AF: 0.00427 AC: 182 AN: 42638

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000377 AC: 3 AN: 79508 Hom.: 0 Cov.: 29 AF XY: 0.0000265 AC XY: 1 AN XY: 37758

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

African (AFR) AF: 0.00 AC: 0 AN: 21850

American (AMR) AF: 0.00 AC: 0 AN: 6904

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 2948

South Asian (SAS) AF: 0.00 AC: 0 AN: 2578

European-Finnish (FIN) AF: 0.000478 AC: 2 AN: 4188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 130

European-Non Finnish (NFE) AF: 0.0000267 AC: 1 AN: 37440

Other (OTH) AF: 0.00 AC: 0 AN: 1018

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=66/34	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;