11-78219453-G-A

Variant names:

• chr11-78219453-G-A
• rs901104
• NM_080491.3:c.1888-38C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_080491.3(GAB2):​c.1888-38C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,602,208 control chromosomes in the GnomAD database, including 28,443 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 (2353 hom., cov: 32)
  • Exomes 𝑓: 0.18 (26090 hom.)
• Consequence: GAB2 NM_080491.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0650
• Publications: 30 publications found

Genes affected

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]

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080491.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAB2	NM_080491.3	MANE Select	c.1888-38C>T		intron	N/A	NP_536739.1
	GAB2	NM_012296.4		c.1774-38C>T		intron	N/A	NP_036428.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAB2	ENST00000361507.5	TSL:1 MANE Select	c.1888-38C>T		intron	N/A	ENSP00000354952.4
	GAB2	ENST00000340149.6	TSL:1	c.1774-38C>T		intron	N/A	ENSP00000343959.2

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23632 AN: 151998 Hom.: 2350 Cov.: 32

Gnomad AFR AF: 0.0609

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.216 AC: 53324 AN: 246502 AF XY: 0.216

Gnomad AFR exome AF: 0.0604

Gnomad AMR exome AF: 0.339

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.379

Gnomad FIN exome AF: 0.194

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.177 AC: 256655 AN: 1450092 Hom.: 26090 Cov.: 28 AF XY: 0.180 AC XY: 129820 AN XY: 721740

African (AFR) AF: 0.0581 AC: 1936 AN: 33318

American (AMR) AF: 0.325 AC: 14491 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 4608 AN: 25896

East Asian (EAS) AF: 0.405 AC: 16045 AN: 39612

South Asian (SAS) AF: 0.286 AC: 24510 AN: 85614

European-Finnish (FIN) AF: 0.193 AC: 10241 AN: 52942

Middle Eastern (MID) AF: 0.273 AC: 1558 AN: 5716

European-Non Finnish (NFE) AF: 0.156 AC: 172166 AN: 1102418

Other (OTH) AF: 0.185 AC: 11100 AN: 59984

GnomAD4 genome AF: 0.155 AC: 23647 AN: 152116 Hom.: 2353 Cov.: 32 AF XY: 0.160 AC XY: 11929 AN XY: 74344

African (AFR) AF: 0.0609 AC: 2531 AN: 41536

American (AMR) AF: 0.234 AC: 3581 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 631 AN: 3470

East Asian (EAS) AF: 0.393 AC: 2024 AN: 5146

South Asian (SAS) AF: 0.276 AC: 1330 AN: 4814

European-Finnish (FIN) AF: 0.201 AC: 2127 AN: 10588

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.161 AC: 10929 AN: 67968

Other (OTH) AF: 0.172 AC: 363 AN: 2110

Alfa AF: 0.171 Hom.: 695

Bravo AF: 0.154

Asia WGS AF: 0.267 AC: 926 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.75
PhyloP100		-0.065
Mutation Taster		=100/0	polymorphism (auto)

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: rs901104; hg19: chr11-77930499; COSMIC: COSV104413130;