11-122794722-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_032873.5(UBASH3B):c.1001C>T(p.Thr334Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000065 in 1,614,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (1 hom.)
• Consequence: UBASH3B NM_032873.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.27

Genes affected

UBASH3B (HGNC:29884): (ubiquitin associated and SH3 domain containing B) This gene encodes a protein that contains a ubiquitin associated domain at the N-terminus, an SH3 domain, and a C-terminal domain with similarities to the catalytic motif of phosphoglycerate mutase. The encoded protein was found to inhibit endocytosis of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14978194).
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBASH3B	NM_032873.5	c.1001C>T	p.Thr334Ile	missense_variant	7/14	ENST00000284273.6
UBASH3B	NM_001363365.2	c.896C>T	p.Thr299Ile	missense_variant	7/14
UBASH3B	XM_005271712.4	c.1085C>T	p.Thr362Ile	missense_variant	7/14
UBASH3B	XM_011543041.3	c.944C>T	p.Thr315Ile	missense_variant	7/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBASH3B	ENST00000284273.6	c.1001C>T	p.Thr334Ile	missense_variant	7/14	1	NM_032873.5	P1
	ENST00000649590.1	n.74-28673G>A		intron_variant, non_coding_transcript_variant
UBASH3B	ENST00000526493.1	n.1089C>T		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251374 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000684 AC: 100 AN: 1461864 Hom.: 1 Cov.: 30 AF XY: 0.0000660 AC XY: 48 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000130 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Apr 26, 2023

The c.1001C>T (p.T334I) alteration is located in exon 7 (coding exon 7) of the UBASH3B gene. This alteration results from a C to T substitution at nucleotide position 1001, causing the threonine (T) at amino acid position 334 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	Benign	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	20
Dann	Benign	0.73
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.17
Sift	Benign	0.070	T
Sift4G	Benign	0.23	T
Polyphen		0.18	B
Vest4		0.54
MutPred		0.24		Loss of disorder (P = 0.0618);
MVP		0.13
MPC		0.54
ClinPred		0.24	T
GERP RS		5.2
Varity_R		0.12
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs558670793; hg19: chr11-122665430;