rs5746832

Variant names:

• chr22-19783667-G-A
• rs5746832
• NM_053004.3:c.*5042C>T

Variant summary

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

The NM_053004.3(GNB1L):​c.*5042C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 159,142 control chromosomes in the GnomAD database, including 15,651 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 0.44 (14951 hom., cov: 33)
  • Exomes 𝑓: 0.43 (700 hom.)
• Consequence: GNB1L NM_053004.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0910
• 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]

TBX1 (HGNC:11592): (T-box transcription factor 1) This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene product shares 98% amino acid sequence identity with the mouse ortholog. DiGeorge syndrome (DGS)/velocardiofacial syndrome (VCFS), a common congenital disorder characterized by neural-crest-related developmental defects, has been associated with deletions of chromosome 22q11.2, where this gene has been mapped. Studies using mouse models of DiGeorge syndrome suggest a major role for this gene in the molecular etiology of DGS/VCFS. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

TBX1 Gene-Disease associations (from GenCC):

• conotruncal heart malformations

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• DiGeorge syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• velocardiofacial syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• 22q11.2 deletion syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNB1L	NM_053004.3	c.*5042C>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000329517.11	NP_443730.1
TBX1	NM_005992.1	c.*364G>A		downstream_gene_variant			NP_005983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNB1L	ENST00000329517.11	c.*5042C>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_053004.3	ENSP00000331313.6
TBX1	ENST00000359500.7	c.*364G>A		downstream_gene_variant		1		ENSP00000352483.3

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66790 AN: 152030 Hom.: 14929 Cov.: 33

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.464

GnomAD4 exome AF: 0.428 AC: 2991 AN: 6994 Hom.: 700 Cov.: 0 AF XY: 0.425 AC XY: 1535 AN XY: 3616

African (AFR) AF: 0.429 AC: 18 AN: 42

American (AMR) AF: 0.501 AC: 685 AN: 1368

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 36 AN: 62

East Asian (EAS) AF: 0.472 AC: 67 AN: 142

South Asian (SAS) AF: 0.456 AC: 250 AN: 548

European-Finnish (FIN) AF: 0.333 AC: 34 AN: 102

Middle Eastern (MID) AF: 0.571 AC: 8 AN: 14

European-Non Finnish (NFE) AF: 0.400 AC: 1765 AN: 4410

Other (OTH) AF: 0.418 AC: 128 AN: 306

GnomAD4 genome AF: 0.439 AC: 66865 AN: 152148 Hom.: 14951 Cov.: 33 AF XY: 0.441 AC XY: 32788 AN XY: 74386

African (AFR) AF: 0.423 AC: 17541 AN: 41514

American (AMR) AF: 0.504 AC: 7706 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 2118 AN: 3472

East Asian (EAS) AF: 0.534 AC: 2768 AN: 5180

South Asian (SAS) AF: 0.506 AC: 2443 AN: 4824

European-Finnish (FIN) AF: 0.349 AC: 3690 AN: 10586

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.427 AC: 28985 AN: 67956

Other (OTH) AF: 0.462 AC: 976 AN: 2112

Alfa AF: 0.441 Hom.: 4422

Bravo AF: 0.450

Asia WGS AF: 0.467 AC: 1624 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.7
DANN	Benign	0.53
PhyloP100		0.091
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: rs5746832; hg19: chr22-19771190;