chr11-78215246-G-A

Position:

• chr11-78215246-G-A

Variant summary

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

The XM_047427334.1(USP35):​c.*43+1390G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 152,518 control chromosomes in the GnomAD database, including 2,565 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2560 hom., cov: 32)
  • Exomes 𝑓: 0.22 (5 hom.)
• Consequence: USP35 XM_047427334.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.154

Genes affected

USP35 (HGNC:20061): (ubiquitin specific peptidase 35) This gene encodes a member of the peptidase C19 family of ubiquitin-specific proteases. These deubiquitinating enzymes (DUBs) catalyze the removal of ubiquitin proteins from other proteins. The encoded protein associates with polarized mitochondria and has been shown to inhibit NF-kappa B activation and delay PARK2-mediated degradation of mitochondria. Expression of this gene is upregulated by the let-7a microRNA and reduced expression has been observed in human tumor tissues. [provided by RefSeq, Jul 2017]

(HGNC:):

GAB2 (HGNC:14458): (GRB2 associated binding protein 2) This gene is a member of the GRB2-associated binding protein (GAB) gene family. These proteins contain pleckstrin homology (PH) domain, and bind SHP2 tyrosine phosphatase and GRB2 adapter protein. They act as adapters for transmitting various signals in response to stimuli through cytokine and growth factor receptors, and T- and B-cell antigen receptors. The protein encoded by this gene is the principal activator of phosphatidylinositol-3 kinase in response to activation of the high affinity IgE receptor. Two alternatively spliced transcripts encoding different isoforms have been described for this gene. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USP35	NM_020798.4	c.*1433G>A		downstream_gene_variant		ENST00000529308.6	NP_065849.1
GAB2	NM_080491.3	c.*4026C>T		downstream_gene_variant		ENST00000361507.5	NP_536739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USP35	ENST00000529308.6	c.*1433G>A		downstream_gene_variant		5	NM_020798.4	ENSP00000431876.1
GAB2	ENST00000361507.5	c.*4026C>T		downstream_gene_variant		1	NM_080491.3	ENSP00000354952.4

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24840 AN: 151966 Hom.: 2556 Cov.: 32

Gnomad AFR AF: 0.0635

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.187

GnomAD4 exome AF: 0.220 AC: 95 AN: 432 Hom.: 5 AF XY: 0.229 AC XY: 60 AN XY: 262

Gnomad4 FIN exome AF: 0.221

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.163 AC: 24856 AN: 152086 Hom.: 2560 Cov.: 32 AF XY: 0.169 AC XY: 12537 AN XY: 74350

Gnomad4 AFR AF: 0.0635

Gnomad4 AMR AF: 0.245

Gnomad4 ASJ AF: 0.199

Gnomad4 EAS AF: 0.395

Gnomad4 SAS AF: 0.293

Gnomad4 FIN AF: 0.202

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.185

Alfa AF: 0.156 Hom.: 398

Bravo AF: 0.163

Asia WGS AF: 0.270 AC: 939 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.55
DANN	Benign	0.45

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2912; hg19: chr11-77926292;