rs117849691

Positions:

• chr20-58903579-G-A
• chr20-58903579-G-C
• chr20-58903579-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_000516.7(GNAS):​c.306G>A​(p.Ala102Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: GNAS NM_000516.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.179

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 20-58903579-G-A is Benign according to our data. Variant chr20-58903579-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 435342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58903579-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.179 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0012 (183/152298) while in subpopulation AFR AF= 0.00399 (166/41556). AF 95% confidence interval is 0.0035. There are 0 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_000516.7	c.306G>A	p.Ala102Ala	synonymous_variant	4/13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*212G>A		3_prime_UTR_variant	4/13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.306G>A	p.Ala102Ala	synonymous_variant	4/13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2238G>A	p.Ala746Ala	synonymous_variant	4/13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2193G>A	p.Ala731Ala	synonymous_variant	3/12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.309G>A	p.Ala103Ala	synonymous_variant	4/13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.264G>A	p.Ala88Ala	synonymous_variant	3/12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.132G>A	p.Ala44Ala	synonymous_variant	4/13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.132G>A	p.Ala44Ala	synonymous_variant	5/14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.132G>A	p.Ala44Ala	synonymous_variant	4/13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.87G>A	p.Ala29Ala	synonymous_variant	3/12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.87G>A	p.Ala29Ala	synonymous_variant	4/13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.87G>A	p.Ala29Ala	synonymous_variant	3/12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.87G>A	p.Ala29Ala	synonymous_variant	3/12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.87G>A	p.Ala29Ala	synonymous_variant	3/12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.87G>A	p.Ala29Ala	synonymous_variant	3/12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.87G>A	p.Ala29Ala	synonymous_variant	3/12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*212G>A		3_prime_UTR_variant	4/13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000461152.6	c.*176G>A		3_prime_UTR_variant	3/3	5		ENSP00000499274.1
GNAS	ENST00000453292.7	c.*167G>A		3_prime_UTR_variant	3/12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 182 AN: 152180 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000302 AC: 76 AN: 251484 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135916

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000160 AC: 234 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.000142 AC XY: 103 AN XY: 727214

Gnomad4 AFR exome AF: 0.00388

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152298 Hom.: 0 Cov.: 31 AF XY: 0.00118 AC XY: 88 AN XY: 74472

Gnomad4 AFR AF: 0.00399

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000399 Hom.: 0

Bravo AF: 0.00131

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	GNAS: BP4, BP7 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 05, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.2
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs117849691; hg19: chr20-57478634; COSMIC: COSV104548840; COSMIC: COSV104548840;