11-118384947-TAAAAAAAAAAAAA-TAAAAAAAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001204077.2(UBE4A):​c.2412+23dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,062,816 control chromosomes in the GnomAD database, including 38 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.036 (37 hom., cov: 29)
  • Exomes 𝑓: 0.014 (1 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0364 (2891/79388) while in subpopulation NFE AF = 0.0381 (1424/37362). AF 95% confidence interval is 0.0365. There are 37 homozygotes in GnomAd4. There are 1362 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0365 AC: 2901 AN: 79398 Hom.: 38 Cov.: 29

Gnomad AFR AF: 0.0383

Gnomad AMI AF: 0.0112

Gnomad AMR AF: 0.0348

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.0105

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0381

Gnomad OTH AF: 0.0373

GnomAD2 exomes AF: 0.0144 AC: 1204 AN: 83660 AF XY: 0.0134

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.0173

Gnomad ASJ exome AF: 0.0132

Gnomad EAS exome AF: 0.0200

Gnomad FIN exome AF: 0.00757

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0144 AC: 14129 AN: 983428 Hom.: 1 Cov.: 0 AF XY: 0.0143 AC XY: 7164 AN XY: 501262

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

African (AFR) AF: 0.0149 AC: 329 AN: 22154

American (AMR) AF: 0.0110 AC: 311 AN: 28346

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 258 AN: 18856

East Asian (EAS) AF: 0.00762 AC: 264 AN: 34642

South Asian (SAS) AF: 0.0179 AC: 1128 AN: 62992

European-Finnish (FIN) AF: 0.0120 AC: 410 AN: 34282

Middle Eastern (MID) AF: 0.0162 AC: 63 AN: 3882

European-Non Finnish (NFE) AF: 0.0146 AC: 10733 AN: 735320

Other (OTH) AF: 0.0147 AC: 633 AN: 42954

⚠️ 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: 0.0364 AC: 2891 AN: 79388 Hom.: 37 Cov.: 29 AF XY: 0.0361 AC XY: 1362 AN XY: 37724

African (AFR) AF: 0.0381 AC: 833 AN: 21876

American (AMR) AF: 0.0345 AC: 238 AN: 6898

Ashkenazi Jewish (ASJ) AF: 0.0507 AC: 101 AN: 1994

East Asian (EAS) AF: 0.0102 AC: 30 AN: 2932

South Asian (SAS) AF: 0.0224 AC: 57 AN: 2544

European-Finnish (FIN) AF: 0.0365 AC: 153 AN: 4188

Middle Eastern (MID) AF: 0.103 AC: 12 AN: 116

European-Non Finnish (NFE) AF: 0.0381 AC: 1424 AN: 37362

Other (OTH) AF: 0.0368 AC: 38 AN: 1032

Alfa AF: 0.00931 Hom.: 14

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=94/6	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

Other links and lift over

dbSNP: rs370025001; hg19: chr11-118255662; COSMIC: COSV104985090;