rs200787839

Variant names:

• chr21-42404046-C-G
• rs200787839
• NM_018961.4:c.101C>G

Your query was ambiguous. Multiple possible variants found:

• chr21-42404046-C-G
• chr21-42404046-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018961.4(UBASH3A):​c.101C>G​(p.Pro34Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000732 in 1,366,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P34L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: UBASH3A NM_018961.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.61
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBASH3A	NM_018961.4	MANE Select	c.101C>G	p.Pro34Arg	missense	Exon 1 of 15	NP_061834.1	P57075-1
	UBASH3A	NM_001001895.3		c.101C>G	p.Pro34Arg	missense	Exon 1 of 14	NP_001001895.1	P57075-2
	UBASH3A	NM_001243467.2		c.101C>G	p.Pro34Arg	missense	Exon 1 of 12	NP_001230396.1	P57075-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBASH3A	ENST00000319294.11	TSL:1 MANE Select	c.101C>G	p.Pro34Arg	missense	Exon 1 of 15	ENSP00000317327.6	P57075-1
	UBASH3A	ENST00000291535.11	TSL:1	c.101C>G	p.Pro34Arg	missense	Exon 1 of 14	ENSP00000291535.6	P57075-2
	UBASH3A	ENST00000398367.1	TSL:1	c.101C>G	p.Pro34Arg	missense	Exon 1 of 12	ENSP00000381408.1	P57075-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.32e-7 AC: 1 AN: 1366386 Hom.: 0 Cov.: 30 AF XY: 0.00000148 AC XY: 1 AN XY: 673632

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29998

American (AMR) AF: 0.00 AC: 0 AN: 33322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24368

East Asian (EAS) AF: 0.00 AC: 0 AN: 33594

South Asian (SAS) AF: 0.00 AC: 0 AN: 75264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4822

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1059978

Other (OTH) AF: 0.00 AC: 0 AN: 56542

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.74		Gain of catalytic residue at P34 (P = 0.0036)
MVP		0.60
MPC		0.62
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		0.042	Neutral
Varity_R		0.66
gMVP		0.53
Mutation Taster		=69/31	polymorphism

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: rs200787839; hg19: chr21-43824155;