11-118368778-G-A

Variant names:

• chr11-118368778-G-A
• rs772231827
• NM_001204077.2:c.269G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001204077.2(UBE4A):​c.269G>A​(p.Arg90Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UBE4A NM_001204077.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.269G>A	p.Arg90Lys	missense	Exon 3 of 20	NP_001191006.1	Q14139-1
	UBE4A	NM_004788.4		c.269G>A	p.Arg90Lys	missense	Exon 3 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.269G>A	p.Arg90Lys	missense	Exon 3 of 20	ENSP00000252108.4	Q14139-1
	UBE4A	ENST00000431736.6	TSL:1	c.269G>A	p.Arg90Lys	missense	Exon 3 of 20	ENSP00000387362.2	Q14139-2
	UBE4A	ENST00000911347.1		c.269G>A	p.Arg90Lys	missense	Exon 3 of 20	ENSP00000581406.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251324 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000205 AC: 3 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.044	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0039	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.24	N
REVEL	Benign	0.22
Sift	Benign	0.61	T
Sift4G	Benign	0.95	T
Polyphen		0.61	P
Vest4		0.78
MutPred		0.56		Gain of ubiquitination at R90 (P = 0.0094)
MVP		0.23
MPC		0.44
ClinPred		0.42	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.65
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs772231827; hg19: chr11-118239493;