Genetic Variant UBE4A:c.2412+17_2412+23delAAAAAAA (chr11-118384947-TAAAAAAA-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_001204077.2(UBE4A):c.2412+17_2412+23delAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,066,638 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 0.000050 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

UBE4A
NM_001204077.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.09

Publications

1 publications found

Variant links:

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

UBE4A links:

LOC100131626 (HGNC:):

LOC100131626 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000503 (4/79514) while in subpopulation EAS AF = 0.00102 (3/2948). AF 95% confidence interval is 0.000277. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
UBE4A	NM_001204077.2 link	c.2412+17_2412+23delAAAAAAA	intron_variant	Intron 15 of 19	ENST00000252108.8	NP_001191006.1
UBE4A	NM_004788.4 link	c.2433+17_2433+23delAAAAAAA	intron_variant	Intron 15 of 19		NP_004779.2
LOC100131626	NR_046369.1 link	n.232-3394_232-3388delTTTTTTT	intron_variant	Intron 3 of 3
LOC100131626	NR_046370.1 link	n.232-3447_232-3441delTTTTTTT	intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
UBE4A	ENST00000252108.8 link	c.2412+3_2412+9delAAAAAAA	splice_region_variant, intron_variant	Intron 15 of 19	1	NM_001204077.2	ENSP00000252108.4	Q14139-1
UBE4A	ENST00000431736.6 link	c.2433+3_2433+9delAAAAAAA	splice_region_variant, intron_variant	Intron 15 of 19	1		ENSP00000387362.2	Q14139-2
UBE4A	ENST00000545354.1 link	c.828+3_828+9delAAAAAAA	splice_region_variant, intron_variant	Intron 6 of 10	2		ENSP00000438918.1	B7Z7P0

Frequencies

GnomAD3 genomes

AF:

0.0000503

AC:

AN:

79514

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00102

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000267

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000171

AC:

169

AN:

987124

Hom.:

AF XY:

0.000171

AC XY:

AN XY:

503288

show subpopulations

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

African (AFR)

AF:

0.000225

AC:

AN:

22232

American (AMR)

AF:

0.000140

AC:

AN:

28588

Ashkenazi Jewish (ASJ)

AF:

0.000158

AC:

AN:

18936

East Asian (EAS)

AF:

0.000173

AC:

AN:

34782

South Asian (SAS)

AF:

0.000126

AC:

AN:

63502

European-Finnish (FIN)

AF:

0.000116

AC:

AN:

34456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3896

European-Non Finnish (NFE)

AF:

0.000179

AC:

132

AN:

737634

Other (OTH)

AF:

0.000162

AC:

AN:

43098

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.257

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000503

AC:

AN:

79514

Hom.:

Cov.:

AF XY:

0.0000530

AC XY:

AN XY:

37762

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21848

American (AMR)

AF:

0.00

AC:

AN:

6906

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2000

East Asian (EAS)

AF:

0.00102

AC:

AN:

2948

South Asian (SAS)

AF:

0.00

AC:

AN:

2578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

130

European-Non Finnish (NFE)

AF:

0.0000267

AC:

AN:

37442

Other (OTH)

AF:

0.00

AC:

AN:

1018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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11-118384947-TAAAAAAAAAAAAA-TAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over