22-19788842-G-A

Variant names:

• chr22-19788842-G-A
• rs73148914
• NM_053004.3:c.851C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T284K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (28 hom., cov: 33)
  • Exomes 𝑓: 0.019 (316 hom.)
• Consequence: GNB1L NM_053004.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.89
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -13 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 VariationId is 3042211.Status of the report is no_assertion_criteria_provided, 0 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053004.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB1L	NM_053004.3	MANE Select	c.851C>T	p.Thr284Met	missense	Exon 8 of 8	NP_443730.1	Q9BYB4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB1L	ENST00000329517.11	TSL:1 MANE Select	c.851C>T	p.Thr284Met	missense	Exon 8 of 8	ENSP00000331313.6	Q9BYB4-1
	GNB1L	ENST00000403325.5	TSL:1	c.851C>T	p.Thr284Met	missense	Exon 7 of 7	ENSP00000385154.1	Q9BYB4-1
	GNB1L	ENST00000405009.5	TSL:1	c.631-216C>T		intron	N/A	ENSP00000384626.1	Q9BYB4-2

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

GnomAD2 exomes AF: 0.0147 AC: 3629 AN: 246342 AF XY: 0.0148

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 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

African (AFR) AF: 0.00299 AC: 100 AN: 33476

American (AMR) AF: 0.00649 AC: 290 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 52 AN: 26104

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39698

South Asian (SAS) AF: 0.000916 AC: 79 AN: 86234

European-Finnish (FIN) AF: 0.0265 AC: 1379 AN: 52136

Middle Eastern (MID) AF: 0.000874 AC: 5 AN: 5724

European-Non Finnish (NFE) AF: 0.0229 AC: 25417 AN: 1111844

Other (OTH) AF: 0.0159 AC: 959 AN: 60326

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

African (AFR) AF: 0.00438 AC: 182 AN: 41594

American (AMR) AF: 0.00679 AC: 104 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.0250 AC: 266 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0251 AC: 1708 AN: 68024

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.0210 Hom.: 101

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

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	GNB1L-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.080
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.9
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.18
Sift	Benign	0.033	D
Sift4G	Uncertain	0.031	D
Polyphen		0.97	D
Vest4		0.12
MPC		0.60
ClinPred		0.048	T
GERP RS		3.4
Varity_R		0.040
gMVP		0.43
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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