rs502514

Variant names:

• chr11-118371280-T-C
• rs502514
• NM_001204077.2:c.409-234T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001204077.2(UBE4A):​c.409-234T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 152,038 control chromosomes in the GnomAD database, including 4,998 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4998 hom., cov: 31)
• Consequence: UBE4A NM_001204077.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.28
• Publications: 13 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204077.2. 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.409-234T>C		intron	N/A	NP_001191006.1
	UBE4A	NM_004788.4		c.409-234T>C		intron	N/A	NP_004779.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE4A	ENST00000252108.8	TSL:1 MANE Select	c.409-234T>C		intron	N/A	ENSP00000252108.4
	UBE4A	ENST00000431736.6	TSL:1	c.409-234T>C		intron	N/A	ENSP00000387362.2
	UBE4A	ENST00000911347.1		c.409-234T>C		intron	N/A	ENSP00000581406.1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35194 AN: 151920 Hom.: 5003 Cov.: 31

Gnomad AFR AF: 0.0656

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.245

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.231 AC: 35171 AN: 152038 Hom.: 4998 Cov.: 31 AF XY: 0.231 AC XY: 17173 AN XY: 74294

African (AFR) AF: 0.0653 AC: 2712 AN: 41502

American (AMR) AF: 0.226 AC: 3455 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 931 AN: 3472

East Asian (EAS) AF: 0.191 AC: 990 AN: 5176

South Asian (SAS) AF: 0.142 AC: 683 AN: 4820

European-Finnish (FIN) AF: 0.329 AC: 3464 AN: 10536

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.323 AC: 21950 AN: 67958

Other (OTH) AF: 0.243 AC: 512 AN: 2110

Alfa AF: 0.256 Hom.: 5548

Bravo AF: 0.218

Asia WGS AF: 0.148 AC: 512 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.6
DANN	Benign	0.59
PhyloP100		2.3
Mutation Taster		=100/0	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: rs502514; hg19: chr11-118241995;