chr22-19788883-G-A

Variant names:

• chr22-19788883-G-A
• rs140821525
• NM_053004.3:c.810C>T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_053004.3(GNB1L):​c.810C>T​(p.Thr270Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00232 in 1,612,894 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (33 hom.)
• Consequence: GNB1L NM_053004.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -4.96

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 22-19788883-G-A is Benign according to our data. Variant chr22-19788883-G-A is described in ClinVar as [Benign]. Clinvar id is 711009.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.96 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00188 (286/152352) while in subpopulation SAS AF= 0.0205 (99/4828). AF 95% confidence interval is 0.0172. There are 2 homozygotes in gnomad4. There are 171 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNB1L	NM_053004.3	c.810C>T	p.Thr270Thr	synonymous_variant	Exon 8 of 8	ENST00000329517.11	NP_443730.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNB1L	ENST00000329517.11	c.810C>T	p.Thr270Thr	synonymous_variant	Exon 8 of 8	1	NM_053004.3	ENSP00000331313.6
GNB1L	ENST00000403325.5	c.810C>T	p.Thr270Thr	synonymous_variant	Exon 7 of 7	1		ENSP00000385154.1
GNB1L	ENST00000405009.5	c.631-257C>T		intron_variant	Intron 7 of 7	1		ENSP00000384626.1
GNB1L	ENST00000460402.5	n.778C>T		non_coding_transcript_exon_variant	Exon 6 of 6	3

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 285 AN: 152234 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00982

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00355 AC: 881 AN: 248228 Hom.: 11 AF XY: 0.00414 AC XY: 559 AN XY: 134862

Gnomad AFR exome AF: 0.000374

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00310

Gnomad EAS exome AF: 0.00777

Gnomad SAS exome AF: 0.0172

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00237 AC: 3455 AN: 1460542 Hom.: 33 Cov.: 32 AF XY: 0.00277 AC XY: 2012 AN XY: 726594

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00325

Gnomad4 EAS exome AF: 0.00826

Gnomad4 SAS exome AF: 0.0164

Gnomad4 FIN exome AF: 0.0000574

Gnomad4 NFE exome AF: 0.00120

Gnomad4 OTH exome AF: 0.00374

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152352 Hom.: 2 Cov.: 33 AF XY: 0.00230 AC XY: 171 AN XY: 74498

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00984

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.00142

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GNB1L-related disorder Benign:1

Feb 20, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.16
DANN	Benign	0.92

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: rs140821525; hg19: chr22-19776406; COSMIC: COSV61548634; COSMIC: COSV61548634;