chr21-42434957-A-G

Variant names:

• chr21-42434957-A-G
• rs1893592
• NM_018961.4:c.1393+3A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018961.4(UBASH3A):​c.1393+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: UBASH3A NM_018961.4 splice_region, intron
• Scores: Splicing: ADA: 0.1166
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.697
• Publications: 99 publications found

Genes affected

UBASH3A (HGNC:12462): (ubiquitin associated and SH3 domain containing A) This gene encodes one of two family members belonging to the T-cell ubiquitin ligand (TULA) family. Both family members can negatively regulate T-cell signaling. This family member can facilitate growth factor withdrawal-induced apoptosis in T cells, which may occur via its interaction with AIF, an apoptosis-inducing factor. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018961.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBASH3A	NM_018961.4	MANE Select	c.1393+3A>G		splice_region intron	N/A	NP_061834.1
	UBASH3A	NM_001001895.3		c.1279+3A>G		splice_region intron	N/A	NP_001001895.1
	UBASH3A	NM_001243467.2		c.1279+3A>G		splice_region intron	N/A	NP_001230396.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBASH3A	ENST00000319294.11	TSL:1 MANE Select	c.1393+3A>G		splice_region intron	N/A	ENSP00000317327.6
	UBASH3A	ENST00000291535.11	TSL:1	c.1279+3A>G		splice_region intron	N/A	ENSP00000291535.6
	UBASH3A	ENST00000398367.1	TSL:1	c.1279+3A>G		splice_region intron	N/A	ENSP00000381408.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251092 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461582 Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6 AN XY: 727084

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

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

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111894

Other (OTH) AF: 0.0000331 AC: 2 AN: 60380

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000196 Hom.: 17377

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.2
DANN	Benign	0.51
PhyloP100		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.12
dbscSNV1_RF	Benign	0.39
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.36		Position offset: 26

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

Other links and lift over

dbSNP: rs1893592; hg19: chr21-43855067;