11-118371624-T-A

Variant names:

• chr11-118371624-T-A
• rs73613946
• NM_001204077.2:c.519T>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS1

The NM_001204077.2(UBE4A):​c.519T>A​(p.Ile173Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,613,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: UBE4A NM_001204077.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.147
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 11-118371624-T-A is Benign according to our data. Variant chr11-118371624-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2642414.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.147 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0009 (137/152280) while in subpopulation AFR AF = 0.0032 (133/41556). AF 95% confidence interval is 0.00276. There are 0 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.519T>A	p.Ile173Ile	synonymous	Exon 5 of 20	NP_001191006.1	Q14139-1
	UBE4A	NM_004788.4		c.519T>A	p.Ile173Ile	synonymous	Exon 5 of 20	NP_004779.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE4A	ENST00000252108.8	TSL:1 MANE Select	c.519T>A	p.Ile173Ile	synonymous	Exon 5 of 20	ENSP00000252108.4	Q14139-1
	UBE4A	ENST00000431736.6	TSL:1	c.519T>A	p.Ile173Ile	synonymous	Exon 5 of 20	ENSP00000387362.2	Q14139-2
	UBE4A	ENST00000911347.1		c.519T>A	p.Ile173Ile	synonymous	Exon 5 of 20	ENSP00000581406.1

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000227 AC: 57 AN: 250916 AF XY: 0.000140

Gnomad AFR exome AF: 0.00320

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000937 AC: 137 AN: 1461376 Hom.: 0 Cov.: 30 AF XY: 0.0000729 AC XY: 53 AN XY: 727016

African (AFR) AF: 0.00376 AC: 126 AN: 33476

American (AMR) AF: 0.0000895 AC: 4 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111972

Other (OTH) AF: 0.000116 AC: 7 AN: 60386

GnomAD4 genome AF: 0.000900 AC: 137 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74470

African (AFR) AF: 0.00320 AC: 133 AN: 41556

American (AMR) AF: 0.000131 AC: 2 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000783 Hom.: 0

Bravo AF: 0.00107

Asia WGS AF: 0.000289 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	8.6
DANN	Benign	0.73
PhyloP100		0.15

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: rs73613946; hg19: chr11-118242339;