chr21-42403991-C-G

Variant names:

• chr21-42403991-C-G
• rs1461524122
• NM_018961.4:c.46C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018961.4(UBASH3A):​c.46C>G​(p.Leu16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,376,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L16F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: UBASH3A NM_018961.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09807804).

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.46C>G	p.Leu16Val	missense	Exon 1 of 15	NP_061834.1	P57075-1
	UBASH3A	NM_001001895.3		c.46C>G	p.Leu16Val	missense	Exon 1 of 14	NP_001001895.1	P57075-2
	UBASH3A	NM_001243467.2		c.46C>G	p.Leu16Val	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.46C>G	p.Leu16Val	missense	Exon 1 of 15	ENSP00000317327.6	P57075-1
	UBASH3A	ENST00000291535.11	TSL:1	c.46C>G	p.Leu16Val	missense	Exon 1 of 14	ENSP00000291535.6	P57075-2
	UBASH3A	ENST00000398367.1	TSL:1	c.46C>G	p.Leu16Val	missense	Exon 1 of 12	ENSP00000381408.1	P57075-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1376364 Hom.: 0 Cov.: 28 AF XY: 0.00000295 AC XY: 2 AN XY: 678870

African (AFR) AF: 0.00 AC: 0 AN: 30340

American (AMR) AF: 0.00 AC: 0 AN: 34110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24674

East Asian (EAS) AF: 0.0000294 AC: 1 AN: 33982

South Asian (SAS) AF: 0.00 AC: 0 AN: 76388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5010

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1066030

Other (OTH) AF: 0.0000176 AC: 1 AN: 56910

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.012	T
Eigen	Benign	0.083
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.085
Sift	Benign	0.53	T
Sift4G	Benign	0.21	T
Polyphen		0.66	P
Vest4		0.12
MutPred		0.22		Loss of helix (P = 0.028)
MVP		0.38
MPC		0.14
ClinPred		0.25	T
GERP RS		5.2
PromoterAI		0.024	Neutral
Varity_R		0.12
gMVP		0.33
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1461524122; hg19: chr21-43824100;