21-42403967-C-T

Variant names:

• chr21-42403967-C-T
• rs146186753
• NM_018961.4:c.22C>T

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.22C>T​(p.Leu8Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,368,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. L8V) 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: Not reported in ClinVar
• Conservation: PhyloP100: 1.70
• Publications: 3 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=0.19023156).

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.22C>T	p.Leu8Phe	missense	Exon 1 of 15	NP_061834.1	P57075-1
	UBASH3A	NM_001001895.3		c.22C>T	p.Leu8Phe	missense	Exon 1 of 14	NP_001001895.1	P57075-2
	UBASH3A	NM_001243467.2		c.22C>T	p.Leu8Phe	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.22C>T	p.Leu8Phe	missense	Exon 1 of 15	ENSP00000317327.6	P57075-1
	UBASH3A	ENST00000291535.11	TSL:1	c.22C>T	p.Leu8Phe	missense	Exon 1 of 14	ENSP00000291535.6	P57075-2
	UBASH3A	ENST00000398367.1	TSL:1	c.22C>T	p.Leu8Phe	missense	Exon 1 of 12	ENSP00000381408.1	P57075-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000724 AC: 1 AN: 138118 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000460

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1368596 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 674948

African (AFR) AF: 0.00 AC: 0 AN: 30036

American (AMR) AF: 0.0000299 AC: 1 AN: 33482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24434

East Asian (EAS) AF: 0.00 AC: 0 AN: 33552

South Asian (SAS) AF: 0.00 AC: 0 AN: 75494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4784

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1061546

Other (OTH) AF: 0.0000177 AC: 1 AN: 56528

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.090
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.36
MutPred		0.23		Loss of disorder (P = 0.0766)
MVP		0.57
MPC		0.53
ClinPred		0.64	D
GERP RS		0.98
PromoterAI		-0.038	Neutral
Varity_R		0.17
gMVP		0.52
Mutation Taster		=86/14	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: rs146186753; hg19: chr21-43824076;