21-42409538-G-T

Position:

• chr21-42409538-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018961.4(UBASH3A):​c.284G>T​(p.Ser95Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBASH3A NM_018961.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

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]

UBASH3A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37159327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBASH3A	NM_018961.4	c.284G>T	p.Ser95Ile	missense_variant	3/15	ENST00000319294.11	NP_061834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBASH3A	ENST00000319294.11	c.284G>T	p.Ser95Ile	missense_variant	3/15	1	NM_018961.4	ENSP00000317327.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 2022

The c.284G>T (p.S95I) alteration is located in exon 3 (coding exon 3) of the UBASH3A gene. This alteration results from a G to T substitution at nucleotide position 284, causing the serine (S) at amino acid position 95 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.;D;.
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	3.3	.;M;M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.8	.;D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.
Vest4		0.96, 0.94, 0.95
MutPred		0.42		Loss of disorder (P = 0.0161);Loss of disorder (P = 0.0161);Loss of disorder (P = 0.0161);Loss of disorder (P = 0.0161);
MVP		0.57
MPC		0.66
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.79
gMVP		0.81

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-43829647;