rs1893592

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr21-42434957-A-C
• chr21-42434957-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018961.4(UBASH3A):​c.1393+3A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,613,522 control chromosomes in the GnomAD database, including 64,482 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4537 hom., cov: 33)
  • Exomes 𝑓: 0.28 (59945 hom.)
• Consequence: UBASH3A NM_018961.4 splice_region, intron
• Scores: Splicing: ADA: 0.8002
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 21-42434957-A-C is Benign according to our data. Variant chr21-42434957-A-C is described in ClinVar as Benign. ClinVar VariationId is 1232058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBASH3A	NM_018961.4	c.1393+3A>C		splice_region_variant, intron_variant	Intron 10 of 14	ENST00000319294.11	NP_061834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBASH3A	ENST00000319294.11	c.1393+3A>C		splice_region_variant, intron_variant	Intron 10 of 14	1	NM_018961.4	ENSP00000317327.6

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33986 AN: 152074 Hom.: 4532 Cov.: 33

Gnomad AFR AF: 0.0734

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.200

GnomAD2 exomes AF: 0.269 AC: 67438 AN: 251092 AF XY: 0.267

Gnomad AFR exome AF: 0.0685

Gnomad AMR exome AF: 0.353

Gnomad ASJ exome AF: 0.0946

Gnomad EAS exome AF: 0.276

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.278

Gnomad OTH exome AF: 0.238

GnomAD4 exome AF: 0.281 AC: 410426 AN: 1461330 Hom.: 59945 Cov.: 34 AF XY: 0.279 AC XY: 202769 AN XY: 726968

African (AFR) AF: 0.0603 AC: 2018 AN: 33460

American (AMR) AF: 0.342 AC: 15294 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.0997 AC: 2605 AN: 26124

East Asian (EAS) AF: 0.261 AC: 10347 AN: 39690

South Asian (SAS) AF: 0.258 AC: 22270 AN: 86200

European-Finnish (FIN) AF: 0.319 AC: 17009 AN: 53360

Middle Eastern (MID) AF: 0.114 AC: 658 AN: 5766

European-Non Finnish (NFE) AF: 0.292 AC: 324848 AN: 1111694

Other (OTH) AF: 0.255 AC: 15377 AN: 60368

GnomAD4 genome AF: 0.223 AC: 34008 AN: 152192 Hom.: 4537 Cov.: 33 AF XY: 0.227 AC XY: 16882 AN XY: 74394

African (AFR) AF: 0.0732 AC: 3041 AN: 41542

American (AMR) AF: 0.281 AC: 4293 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 357 AN: 3472

East Asian (EAS) AF: 0.268 AC: 1391 AN: 5186

South Asian (SAS) AF: 0.264 AC: 1270 AN: 4814

European-Finnish (FIN) AF: 0.331 AC: 3504 AN: 10572

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.287 AC: 19495 AN: 67996

Other (OTH) AF: 0.198 AC: 417 AN: 2110

Alfa AF: 0.250 Hom.: 17377

Bravo AF: 0.213

Asia WGS AF: 0.256 AC: 894 AN: 3478

EpiCase AF: 0.260

EpiControl AF: 0.262

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 23, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29491471) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.5
DANN	Benign	0.51
PhyloP100		0.70
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.80
dbscSNV1_RF	Benign	0.53
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.53		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; COSMIC: COSV52311220;