chr21-42403997-A-G

Position:

• chr21-42403997-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000319294.11(UBASH3A):​c.52A>G​(p.Ser18Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 1,518,038 control chromosomes in the GnomAD database, including 297,364 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.60 (27325 hom., cov: 32)
  • Exomes 𝑓: 0.63 (270039 hom.)
• Consequence: UBASH3A ENST00000319294.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.849

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.6113288E-5).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBASH3A	NM_018961.4	c.52A>G	p.Ser18Gly	missense_variant	1/15	ENST00000319294.11	NP_061834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBASH3A	ENST00000319294.11	c.52A>G	p.Ser18Gly	missense_variant	1/15	1	NM_018961.4	ENSP00000317327

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90453 AN: 151944 Hom.: 27304 Cov.: 32

Gnomad AFR AF: 0.572

Gnomad AMI AF: 0.656

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.525

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.648

Gnomad OTH AF: 0.607

GnomAD3 exomes AF: 0.546 AC: 74867 AN: 137142 Hom.: 21308 AF XY: 0.555 AC XY: 40280 AN XY: 72562

Gnomad AFR exome AF: 0.515

Gnomad AMR exome AF: 0.388

Gnomad ASJ exome AF: 0.648

Gnomad EAS exome AF: 0.400

Gnomad SAS exome AF: 0.538

Gnomad FIN exome AF: 0.539

Gnomad NFE exome AF: 0.625

Gnomad OTH exome AF: 0.573

GnomAD4 exome AF: 0.625 AC: 853861 AN: 1365976 Hom.: 270039 Cov.: 43 AF XY: 0.624 AC XY: 420455 AN XY: 673308

Gnomad4 AFR exome AF: 0.559

Gnomad4 AMR exome AF: 0.415

Gnomad4 ASJ exome AF: 0.649

Gnomad4 EAS exome AF: 0.440

Gnomad4 SAS exome AF: 0.553

Gnomad4 FIN exome AF: 0.548

Gnomad4 NFE exome AF: 0.648

Gnomad4 OTH exome AF: 0.613

GnomAD4 genome AF: 0.595 AC: 90515 AN: 152062 Hom.: 27325 Cov.: 32 AF XY: 0.585 AC XY: 43444 AN XY: 74326

Gnomad4 AFR AF: 0.572

Gnomad4 AMR AF: 0.511

Gnomad4 ASJ AF: 0.650

Gnomad4 EAS AF: 0.472

Gnomad4 SAS AF: 0.553

Gnomad4 FIN AF: 0.525

Gnomad4 NFE AF: 0.648

Gnomad4 OTH AF: 0.603

Alfa AF: 0.635 Hom.: 55924

Bravo AF: 0.591

TwinsUK AF: 0.643 AC: 2384

ALSPAC AF: 0.651 AC: 2508

ESP6500AA AF: 0.576 AC: 2467

ESP6500EA AF: 0.651 AC: 5382

ExAC AF: 0.463 AC: 39832

Asia WGS AF: 0.481 AC: 1670 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.022	T;.;T;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.043	T;T;T;T
MetaRNN	Benign	0.000026	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.81	.;N;N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.55	.;N;N;N
REVEL	Benign	0.057
Sift	Benign	0.96	.;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.070, 0.030, 0.074
MPC		0.12
ClinPred		0.0047	T
GERP RS		3.4
Varity_R		0.049
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs2277798; hg19: chr21-43824106; COSMIC: COSV52311938;