rs8386

Positions:

• chr20-58910757-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000516.7(GNAS):​c.1113C>T​(p.Asn371Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,613,866 control chromosomes in the GnomAD database, including 1,341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (633 hom., cov: 32)
  • Exomes 𝑓: 0.016 (708 hom.)
• Consequence: GNAS NM_000516.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.08

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 20-58910757-C-T is Benign according to our data. Variant chr20-58910757-C-T is described in ClinVar as [Benign]. Clinvar id is 1166174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58910757-C-T is described in Lovd as [Benign]. Variant chr20-58910757-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=3.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_000516.7	c.1113C>T	p.Asn371Asn	synonymous_variant	13/13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*1019C>T		3_prime_UTR_variant	13/13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.1113C>T	p.Asn371Asn	synonymous_variant	13/13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.3045C>T	p.Asn1015Asn	synonymous_variant	13/13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.3000C>T	p.Asn1000Asn	synonymous_variant	12/12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.1116C>T	p.Asn372Asn	synonymous_variant	13/13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.1071C>T	p.Asn357Asn	synonymous_variant	12/12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.939C>T	p.Asn313Asn	synonymous_variant	13/13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.939C>T	p.Asn313Asn	synonymous_variant	14/14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.939C>T	p.Asn313Asn	synonymous_variant	13/13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.894C>T	p.Asn298Asn	synonymous_variant	12/12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.894C>T	p.Asn298Asn	synonymous_variant	13/13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.894C>T	p.Asn298Asn	synonymous_variant	12/12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.894C>T	p.Asn298Asn	synonymous_variant	12/12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.894C>T	p.Asn298Asn	synonymous_variant	12/12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.894C>T	p.Asn298Asn	synonymous_variant	12/12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.894C>T	p.Asn298Asn	synonymous_variant	12/12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*1019C>T		3_prime_UTR_variant	13/13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*974C>T		3_prime_UTR_variant	12/12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.0568 AC: 8645 AN: 152148 Hom.: 633 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0253

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.0359

GnomAD3 exomes AF: 0.0218 AC: 5490 AN: 251460 Hom.: 280 AF XY: 0.0189 AC XY: 2571 AN XY: 135910

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.0199

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0108

Gnomad FIN exome AF: 0.00323

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0162 AC: 23698 AN: 1461600 Hom.: 708 Cov.: 32 AF XY: 0.0157 AC XY: 11394 AN XY: 727122

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.0154

Gnomad4 ASJ exome AF: 0.0212

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0109

Gnomad4 FIN exome AF: 0.00300

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.0213

GnomAD4 genome AF: 0.0568 AC: 8655 AN: 152266 Hom.: 633 Cov.: 32 AF XY: 0.0552 AC XY: 4113 AN XY: 74456

Gnomad4 AFR AF: 0.171

Gnomad4 AMR AF: 0.0252

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.00386

Gnomad4 NFE AF: 0.0131

Gnomad4 OTH AF: 0.0355

Alfa AF: 0.0263 Hom.: 244

Bravo AF: 0.0628

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.0164

EpiControl AF: 0.0157

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs8386; hg19: chr20-57485812; COSMIC: COSV55686986; COSMIC: COSV55686986;