22-19802018-A-C

Position:

• chr22-19802018-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_053004.3(GNB1L):​c.715T>G​(p.Trp239Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,593,300 control chromosomes in the GnomAD database, including 19,065 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1745 hom., cov: 33)
  • Exomes 𝑓: 0.13 (17320 hom.)
• Consequence: GNB1L NM_053004.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.93

Genes affected

GNB1L (HGNC:4397): (G protein subunit beta 1 like) This gene encodes a G-protein beta-subunit-like polypeptide which is a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This protein contains 6 WD repeats and is highly expressed in the heart. The gene maps to the region on chromosome 22q11, which is deleted in DiGeorge syndrome, trisomic in derivative 22 syndrome and tetrasomic in cat-eye syndrome. Therefore, this gene may contribute to the etiology of those disorders. Transcripts from this gene share exons with some transcripts from the C22orf29 gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016080439).
• BP6: Variant 22-19802018-A-C is Benign according to our data. Variant chr22-19802018-A-C is described in ClinVar as [Benign]. Clinvar id is 3060781.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNB1L	NM_053004.3	c.715T>G	p.Trp239Gly	missense_variant	7/8	ENST00000329517.11	NP_443730.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNB1L	ENST00000329517.11	c.715T>G	p.Trp239Gly	missense_variant	7/8	1	NM_053004.3	ENSP00000331313	P1

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18259 AN: 152184 Hom.: 1742 Cov.: 33

Gnomad AFR AF: 0.0430

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.479

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.0594

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.127

GnomAD3 exomes AF: 0.176 AC: 37855 AN: 215230 Hom.: 4736 AF XY: 0.174 AC XY: 20256 AN XY: 116554

Gnomad AFR exome AF: 0.0407

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.479

Gnomad SAS exome AF: 0.213

Gnomad FIN exome AF: 0.0584

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.149

GnomAD4 exome AF: 0.134 AC: 193182 AN: 1440998 Hom.: 17320 Cov.: 33 AF XY: 0.137 AC XY: 97822 AN XY: 715238

Gnomad4 AFR exome AF: 0.0402

Gnomad4 AMR exome AF: 0.286

Gnomad4 ASJ exome AF: 0.203

Gnomad4 EAS exome AF: 0.501

Gnomad4 SAS exome AF: 0.211

Gnomad4 FIN exome AF: 0.0605

Gnomad4 NFE exome AF: 0.114

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.120 AC: 18270 AN: 152302 Hom.: 1745 Cov.: 33 AF XY: 0.125 AC XY: 9307 AN XY: 74470

Gnomad4 AFR AF: 0.0432

Gnomad4 AMR AF: 0.219

Gnomad4 ASJ AF: 0.213

Gnomad4 EAS AF: 0.479

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.0594

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.125

Alfa AF: 0.118 Hom.: 1205

Bravo AF: 0.127

TwinsUK AF: 0.113 AC: 418

ALSPAC AF: 0.109 AC: 420

ESP6500AA AF: 0.0391 AC: 172

ESP6500EA AF: 0.113 AC: 968

ExAC AF: 0.155 AC: 18662

Asia WGS AF: 0.292 AC: 1016 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

GNB1L-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.028
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	16
DANN	Benign	0.74
DEOGEN2	Benign	0.039	T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.017	.;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.4	N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.9	N;N
REVEL	Benign	0.058
Sift	Benign	0.54	T;T
Sift4G	Benign	0.80	T;T
Polyphen		0.0	B;B
Vest4		0.049
MPC		0.38
ClinPred		0.0010	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.079
gMVP		0.30

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: rs2073770; hg19: chr22-19789541; COSMIC: COSV61548313;