rs8386

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_080425.4(GNAS):c.3042C>T(p.Asn1014Asn) 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_080425.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.08

Publications

28 publications found

Variant links:

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

GNAS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 1166174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein
GNAS	NM_080425.4 link	c.3042C>T	p.Asn1014Asn	synonymous_variant	Exon 13 of 13	ENST00000371100.9	NP_536350.2
GNAS	NM_000516.7 link	c.1113C>T	p.Asn371Asn	synonymous_variant	Exon 13 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5 link	c.*1019C>T		3_prime_UTR_variant	Exon 13 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GNAS	ENST00000371100.9 link	c.3042C>T	p.Asn1014Asn	synonymous_variant	Exon 13 of 13	5	NM_080425.4	ENSP00000360141.3
GNAS	ENST00000371085.8 link	c.1113C>T	p.Asn371Asn	synonymous_variant	Exon 13 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2 link	c.3045C>T	p.Asn1015Asn	synonymous_variant	Exon 13 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8 link	c.3000C>T	p.Asn1000Asn	synonymous_variant	Exon 12 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12 link	c.1116C>T	p.Asn372Asn	synonymous_variant	Exon 13 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7 link	c.1071C>T	p.Asn357Asn	synonymous_variant	Exon 12 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6 link	c.939C>T	p.Asn313Asn	synonymous_variant	Exon 13 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6 link	c.939C>T	p.Asn313Asn	synonymous_variant	Exon 14 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2 link	c.939C>T	p.Asn313Asn	synonymous_variant	Exon 13 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6 link	c.894C>T	p.Asn298Asn	synonymous_variant	Exon 12 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6 link	c.894C>T	p.Asn298Asn	synonymous_variant	Exon 13 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6 link	c.894C>T	p.Asn298Asn	synonymous_variant	Exon 12 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6 link	c.894C>T	p.Asn298Asn	synonymous_variant	Exon 12 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6 link	c.894C>T	p.Asn298Asn	synonymous_variant	Exon 12 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6 link	c.894C>T	p.Asn298Asn	synonymous_variant	Exon 12 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6 link	c.894C>T	p.Asn298Asn	synonymous_variant	Exon 12 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7 link	c.*1019C>T		3_prime_UTR_variant	Exon 13 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7 link	c.*974C>T		3_prime_UTR_variant	Exon 12 of 12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes

AF:

0.0568

AC:

8645

AN:

152148

Hom.:

633

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0218

AC:

5490

AN:

251460

AF XY:

0.0189

show subpopulations

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 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.:

AF XY:

0.0157

AC XY:

11394

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.180

AC:

6038

AN:

33470

American (AMR)

AF:

0.0154

AC:

689

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0212

AC:

555

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39694

South Asian (SAS)

AF:

0.0109

AC:

936

AN:

86258

European-Finnish (FIN)

AF:

0.00300

AC:

160

AN:

53420

Middle Eastern (MID)

AF:

0.0366

AC:

211

AN:

5768

European-Non Finnish (NFE)

AF:

0.0124

AC:

13821

AN:

1111744

Other (OTH)

AF:

0.0213

AC:

1285

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1207

2415

3622

4830

6037

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

612

1224

1836

2448

3060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0568

AC:

8655

AN:

152266

Hom.:

633

Cov.:

AF XY:

0.0552

AC XY:

4113

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.171

AC:

7117

AN:

41520

American (AMR)

AF:

0.0252

AC:

386

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0110

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00386

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0131

AC:

891

AN:

68032

Other (OTH)

AF:

0.0355

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

391

782

1174

1565

1956

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0259

Hom.:

500

Bravo

AF:

0.0628

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0164

EpiControl

AF:

0.0157

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over