11-118384947-TAAAAAAAAAAAAA-TAAAAAAAAAAAA

Variant names:

• chr11-118384947-TA-T
• rs370025001
• NM_001204077.2:c.2412+23delA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001204077.2(UBE4A):​c.2412+23delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 1,056,106 control chromosomes in the GnomAD database, including 244 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (180 hom., cov: 29)
  • Exomes 𝑓: 0.20 (64 hom.)
• Consequence: UBE4A NM_001204077.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 11-118384947-TA-T is Benign according to our data. Variant chr11-118384947-TA-T is described in ClinVar as Benign. ClinVar VariationId is 403581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0895 AC: 7114 AN: 79474 Hom.: 178 Cov.: 29

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0614

Gnomad ASJ AF: 0.0520

Gnomad EAS AF: 0.0288

Gnomad SAS AF: 0.0423

Gnomad FIN AF: 0.0895

Gnomad MID AF: 0.0846

Gnomad NFE AF: 0.0670

Gnomad OTH AF: 0.0866

GnomAD2 exomes AF: 0.135 AC: 11307 AN: 83660 AF XY: 0.132

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.131

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.201 AC: 195925 AN: 976640 Hom.: 64 Cov.: 0 AF XY: 0.197 AC XY: 98262 AN XY: 497596

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

African (AFR) AF: 0.205 AC: 4495 AN: 21944

American (AMR) AF: 0.137 AC: 3849 AN: 28104

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 3274 AN: 18652

East Asian (EAS) AF: 0.173 AC: 5952 AN: 34492

South Asian (SAS) AF: 0.159 AC: 9932 AN: 62336

European-Finnish (FIN) AF: 0.162 AC: 5513 AN: 33938

Middle Eastern (MID) AF: 0.230 AC: 887 AN: 3860

European-Non Finnish (NFE) AF: 0.210 AC: 153620 AN: 730746

Other (OTH) AF: 0.197 AC: 8403 AN: 42568

⚠️ 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: 0.0897 AC: 7125 AN: 79466 Hom.: 180 Cov.: 29 AF XY: 0.0893 AC XY: 3372 AN XY: 37758

African (AFR) AF: 0.156 AC: 3422 AN: 21894

American (AMR) AF: 0.0614 AC: 423 AN: 6884

Ashkenazi Jewish (ASJ) AF: 0.0520 AC: 104 AN: 2000

East Asian (EAS) AF: 0.0290 AC: 85 AN: 2934

South Asian (SAS) AF: 0.0427 AC: 109 AN: 2550

European-Finnish (FIN) AF: 0.0895 AC: 375 AN: 4188

Middle Eastern (MID) AF: 0.0862 AC: 10 AN: 116

European-Non Finnish (NFE) AF: 0.0670 AC: 2506 AN: 37418

Other (OTH) AF: 0.0883 AC: 91 AN: 1030

Alfa AF: 0.00505 Hom.: 14

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jun 11, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Outside ROI, Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs370025001; hg19: chr11-118255662; COSMIC: COSV52803602;