22-19788842-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_053004.3(GNB1L):c.851C>T(p.Thr284Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,612,600 control chromosomes in the GnomAD database, including 344 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (28 hom., cov: 33)
  • Exomes 𝑓: 0.019 (316 hom.)
• Consequence: GNB1L NM_053004.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.89

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046129823).
• BP6: Variant 22-19788842-G-A is Benign according to our data. Variant chr22-19788842-G-A is described in ClinVar as [Benign]. Clinvar id is 3042211.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0152 (2314/152362) while in subpopulation NFE AF= 0.0251 (1708/68024). AF 95% confidence interval is 0.0241. There are 28 homozygotes in gnomad4. There are 1056 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNB1L	NM_053004.3	c.851C>T	p.Thr284Met	missense_variant	8/8	ENST00000329517.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNB1L	ENST00000329517.11	c.851C>T	p.Thr284Met	missense_variant	8/8	1	NM_053004.3	P1
GNB1L	ENST00000403325.5	c.851C>T	p.Thr284Met	missense_variant	7/7	1		P1
GNB1L	ENST00000405009.5	c.631-216C>T		intron_variant		1
GNB1L	ENST00000460402.5	n.819C>T		non_coding_transcript_exon_variant	6/6	3

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2314 AN: 152244 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.00439

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00680

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0251

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0147 AC: 3629 AN: 246342 Hom.: 53 AF XY: 0.0148 AC XY: 1983 AN XY: 134358

Gnomad AFR exome AF: 0.00349

Gnomad AMR exome AF: 0.00599

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.000442

Gnomad SAS exome AF: 0.000818

Gnomad FIN exome AF: 0.0259

Gnomad NFE exome AF: 0.0242

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0194 AC: 28291 AN: 1460238 Hom.: 316 Cov.: 32 AF XY: 0.0189 AC XY: 13713 AN XY: 726468

Gnomad4 AFR exome AF: 0.00299

Gnomad4 AMR exome AF: 0.00649

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.000916

Gnomad4 FIN exome AF: 0.0265

Gnomad4 NFE exome AF: 0.0229

Gnomad4 OTH exome AF: 0.0159

GnomAD4 genome AF: 0.0152 AC: 2314 AN: 152362 Hom.: 28 Cov.: 33 AF XY: 0.0142 AC XY: 1056 AN XY: 74506

Gnomad4 AFR AF: 0.00438

Gnomad4 AMR AF: 0.00679

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0250

Gnomad4 NFE AF: 0.0251

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0207 Hom.: 49

Bravo AF: 0.0132

TwinsUK AF: 0.0251 AC: 93

ALSPAC AF: 0.0234 AC: 90

ESP6500AA AF: 0.00434 AC: 19

ESP6500EA AF: 0.0242 AC: 207

ExAC AF: 0.0148 AC: 1793

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.0208

EpiControl AF: 0.0184

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GNB1L-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 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	0.13
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	0.080
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.88	D
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.18
Sift	Benign	0.033	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		0.97	D;D
Vest4		0.12
MPC		0.60
ClinPred		0.048	T
GERP RS		3.4
Varity_R		0.040
gMVP		0.43

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: rs73148914; hg19: chr22-19776365; COSMIC: COSV99051957; COSMIC: COSV99051957;