11-62707720-G-A

Position:

• chr11-62707720-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012202.5(GNG3):​c.-197G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 325,964 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (11 hom., cov: 33)
  • Exomes 𝑓: 0.016 (41 hom.)
• Consequence: GNG3 NM_012202.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.434

Genes affected

GNG3 (HGNC:4405): (G protein subunit gamma 3) Guanine nucleotide binding proteins are heterotrimeric signal-transducing molecules consisting of alpha, beta, and gamma subunits. The gamma subunit determines the specificity of which signaling pathways will be affected by this particular complex. The protein encoded by this gene represents the gamma subunit of both inhibitory and stimulatory complexes. [provided by RefSeq, Jan 2012]

BSCL2 (HGNC:15832): (BSCL2 lipid droplet biogenesis associated, seipin) This gene encodes the multi-pass transmembrane protein protein seipin. This protein localizes to the endoplasmic reticulum and may be important for lipid droplet morphology. Mutations in this gene have been associated with congenital generalized lipodystrophy type 2 or Berardinelli-Seip syndrome, a rare autosomal recessive disease characterized by a near absence of adipose tissue and severe insulin resistance. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. Naturally occurring read-through transcription occurs between this locus and the neighboring locus HNRNPUL2 (heterogeneous nuclear ribonucleoprotein U-like 2).[provided by RefSeq, Mar 2011]

HNRNPUL2-BSCL2 (HGNC:49189): (HNRNPUL2-BSCL2 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring HNRNPUL2 (heterogeneous nuclear ribonucleoprotein U-like 2) and BSCL2 (Berardinelli-Seip congenital lipodystrophy 2 (seipin)) genes on chromosome 11. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 11-62707720-G-A is Benign according to our data. Variant chr11-62707720-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1198651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00988 (1505/152328) while in subpopulation SAS AF= 0.0358 (173/4828). AF 95% confidence interval is 0.0315. There are 11 homozygotes in gnomad4. There are 806 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1505 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNG3	NM_012202.5	c.-197G>A		5_prime_UTR_variant	1/3	ENST00000294117.6	NP_036334.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNG3	ENST00000294117	c.-197G>A		5_prime_UTR_variant	1/3	1	NM_012202.5	ENSP00000294117.5
HNRNPUL2-BSCL2	ENST00000403734.2	n.2164-396C>T		intron_variant		2		ENSP00000456010.1

Frequencies

GnomAD3 genomes AF: 0.00987 AC: 1503 AN: 152210 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0354

Gnomad FIN AF: 0.0186

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00908

GnomAD4 exome AF: 0.0158 AC: 2745 AN: 173636 Hom.: 41 Cov.: 0 AF XY: 0.0177 AC XY: 1648 AN XY: 93344

Gnomad4 AFR exome AF: 0.00135

Gnomad4 AMR exome AF: 0.00285

Gnomad4 ASJ exome AF: 0.0348

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0346

Gnomad4 FIN exome AF: 0.0177

Gnomad4 NFE exome AF: 0.0129

Gnomad4 OTH exome AF: 0.0143

GnomAD4 genome AF: 0.00988 AC: 1505 AN: 152328 Hom.: 11 Cov.: 33 AF XY: 0.0108 AC XY: 806 AN XY: 74500

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.0282

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0358

Gnomad4 FIN AF: 0.0186

Gnomad4 NFE AF: 0.0128

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.0118 Hom.: 2

Bravo AF: 0.00743

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs150524831; hg19: chr11-62475192;