rs6092704

Variant names:

• chr20-58893423-A-C
• rs6092704
• NM_080425.4:c.2069-2189A>C

Variant summary

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

The NM_080425.4(GNAS):​c.2069-2189A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,132 control chromosomes in the GnomAD database, including 2,788 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 0.15 (2788 hom., cov: 32)
• Consequence: GNAS NM_080425.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.767
• Publications: 14 publications found

Genes affected

GNAS (HGNC:4392): (GNAS complex locus) This locus has a highly complex imprinted expression pattern. It gives rise to maternally, paternally, and biallelically expressed transcripts that are derived from four alternative promoters and 5' exons. Some transcripts contain a differentially methylated region (DMR) at their 5' exons, and this DMR is commonly found in imprinted genes and correlates with transcript expression. An antisense transcript is produced from an overlapping locus on the opposite strand. One of the transcripts produced from this locus, and the antisense transcript, are paternally expressed noncoding RNAs, and may regulate imprinting in this region. In addition, one of the transcripts contains a second overlapping ORF, which encodes a structurally unrelated protein - Alex. Alternative splicing of downstream exons is also observed, which results in different forms of the stimulatory G-protein alpha subunit, a key element of the classical signal transduction pathway linking receptor-ligand interactions with the activation of adenylyl cyclase and a variety of cellular reponses. Multiple transcript variants encoding different isoforms have been found for this gene. Mutations in this gene result in pseudohypoparathyroidism type 1a, pseudohypoparathyroidism type 1b, Albright hereditary osteodystrophy, pseudopseudohypoparathyroidism, McCune-Albright syndrome, progressive osseus heteroplasia, polyostotic fibrous dysplasia of bone, and some pituitary tumors. [provided by RefSeq, Aug 2012]

GNAS Gene-Disease associations (from GenCC):

• McCune-Albright syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• progressive osseous heteroplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, NO_KNOWN Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pseudohypoparathyroidism type 1B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• pseudohypoparathyroidism type 1C

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• pseudopseudohypoparathyroidism

  Inheritance: AD, Mitochondrial Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• pseudohypoparathyroidism type 1A

  Inheritance: Mitochondrial, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_080425.4	c.2069-2189A>C		intron_variant	Intron 1 of 12	ENST00000371100.9	NP_536350.2
GNAS	NM_000516.7	c.139+1558A>C		intron_variant	Intron 1 of 12	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*43-2189A>C		intron_variant	Intron 1 of 12	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371100.9	c.2069-2189A>C		intron_variant	Intron 1 of 12	5	NM_080425.4	ENSP00000360141.3
GNAS	ENST00000371085.8	c.139+1558A>C		intron_variant	Intron 1 of 12	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000371075.7	c.*43-2189A>C		intron_variant	Intron 1 of 12	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2069-2189A>C		intron_variant	Intron 1 of 12			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2069-2189A>C		intron_variant	Intron 1 of 11	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.139+1558A>C		intron_variant	Intron 1 of 12	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.139+1558A>C		intron_variant	Intron 1 of 11	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.-38-2189A>C		intron_variant	Intron 1 of 12	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.-38-2189A>C		intron_variant	Intron 2 of 13	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.-38-2189A>C		intron_variant	Intron 1 of 12			ENSP00000499353.2
GNAS	ENST00000462499.6	c.-38-2189A>C		intron_variant	Intron 1 of 11	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.-38-2189A>C		intron_variant	Intron 2 of 12	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.-38-2189A>C		intron_variant	Intron 1 of 11	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.-38-2189A>C		intron_variant	Intron 1 of 11	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.-38-2189A>C		intron_variant	Intron 1 of 11	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.-38-2189A>C		intron_variant	Intron 1 of 11	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.-39+1214A>C		intron_variant	Intron 1 of 11	3		ENSP00000499443.2
GNAS	ENST00000461152.6	c.*52-2189A>C		intron_variant	Intron 1 of 2	5		ENSP00000499274.1
GNAS	ENST00000453292.7	c.*43-2189A>C		intron_variant	Intron 1 of 11	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23073 AN: 152014 Hom.: 2787 Cov.: 32

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.0463

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0894

Gnomad EAS AF: 0.00635

Gnomad SAS AF: 0.0573

Gnomad FIN AF: 0.0571

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0881

Gnomad OTH AF: 0.150

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.152 AC: 23105 AN: 152132 Hom.: 2788 Cov.: 32 AF XY: 0.148 AC XY: 11012 AN XY: 74384

African (AFR) AF: 0.335 AC: 13870 AN: 41442

American (AMR) AF: 0.106 AC: 1619 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0894 AC: 310 AN: 3468

East Asian (EAS) AF: 0.00637 AC: 33 AN: 5182

South Asian (SAS) AF: 0.0578 AC: 279 AN: 4826

European-Finnish (FIN) AF: 0.0571 AC: 605 AN: 10602

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0881 AC: 5991 AN: 68006

Other (OTH) AF: 0.149 AC: 316 AN: 2116

Alfa AF: 0.117 Hom.: 2780

Bravo AF: 0.164

Asia WGS AF: 0.0460 AC: 159 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.78
PhyloP100		0.77
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: rs6092704; hg19: chr20-57468478;