rs3730168

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000516.7(GNAS):c.432+93G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,361,808 control chromosomes in the GnomAD database, including 75,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 9821 hom., cov: 32)

Exomes 𝑓: 0.33 ( 65522 hom. )

Consequence

GNAS
NM_000516.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.788

Publications

18 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 20-58903884-G-A is Benign according to our data. Variant chr20-58903884-G-A is described in ClinVar as Benign. ClinVar VariationId is 1238617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7 link	c.432+93G>A		intron_variant	Intron 5 of 12	ENST00000371085.8	NP_000507.1	P63092-1O95467A0A0S2Z3H8
GNAS	NM_016592.5 link	c.*338+93G>A		intron_variant	Intron 5 of 12	ENST00000371075.7	NP_057676.1	O95467-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GNAS	ENST00000371085.8 link	c.432+93G>A	intron_variant	Intron 5 of 12	1	NM_000516.7	ENSP00000360126.3	P63092-1
GNAS	ENST00000371075.7 link	c.*338+93G>A	intron_variant	Intron 5 of 12	1	NM_016592.5	ENSP00000360115.3	O95467-1
GNAS	ENST00000676826.2 link	c.2364+93G>A	intron_variant	Intron 5 of 12			ENSP00000504675.2	A0A7I2V5R6
GNAS	ENST00000371102.8 link	c.2319+93G>A	intron_variant	Intron 4 of 11	5		ENSP00000360143.4	Q5JWF2-2
GNAS	ENST00000354359.12 link	c.435+93G>A	intron_variant	Intron 5 of 12	1		ENSP00000346328.7	P63092-4
GNAS	ENST00000371095.7 link	c.390+93G>A	intron_variant	Intron 4 of 11	1		ENSP00000360136.3	P63092-2
GNAS	ENST00000470512.6 link	c.258+93G>A	intron_variant	Intron 5 of 12	5		ENSP00000499552.2	A0A590UJQ9
GNAS	ENST00000480232.6 link	c.258+93G>A	intron_variant	Intron 6 of 13	5		ENSP00000499545.2	A0A590UJQ9
GNAS	ENST00000663479.2 link	c.258+93G>A	intron_variant	Intron 5 of 12			ENSP00000499353.2	A0A590UJQ9
GNAS	ENST00000462499.6 link	c.213+93G>A	intron_variant	Intron 4 of 11	2		ENSP00000499758.2	A0A590UK28
GNAS	ENST00000467227.6 link	c.213+93G>A	intron_variant	Intron 5 of 12	3		ENSP00000499681.2	A0A590UK28
GNAS	ENST00000478585.6 link	c.213+93G>A	intron_variant	Intron 4 of 11	2		ENSP00000499762.2	A0A590UK28
GNAS	ENST00000481039.6 link	c.213+93G>A	intron_variant	Intron 4 of 11	5		ENSP00000499767.2	A0A590UK28
GNAS	ENST00000485673.6 link	c.213+93G>A	intron_variant	Intron 4 of 11	5		ENSP00000499334.2	A0A590UK28
GNAS	ENST00000488546.6 link	c.213+93G>A	intron_variant	Intron 4 of 11	5		ENSP00000499332.2	A0A590UK28
GNAS	ENST00000492907.6 link	c.213+93G>A	intron_variant	Intron 4 of 11	3		ENSP00000499443.2	A0A590UK28
GNAS	ENST00000453292.7 link	c.*293+93G>A	intron_variant	Intron 4 of 11	5		ENSP00000392000.2	O95467-1A2A2S1

Frequencies

GnomAD3 genomes

AF:

0.353

AC:

53636

AN:

151976

Hom.:

9803

Cov.:

show subpopulations

Gnomad AFR

AF:

0.454

Gnomad AMI

AF:

0.322

Gnomad AMR

AF:

0.324

Gnomad ASJ

AF:

0.323

Gnomad EAS

AF:

0.267

Gnomad SAS

AF:

0.324

Gnomad FIN

AF:

0.292

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.318

Gnomad OTH

AF:

0.340

GnomAD4 exome

AF:

0.325

AC:

393706

AN:

1209714

Hom.:

65522

AF XY:

0.326

AC XY:

200045

AN XY:

613274

show subpopulations

African (AFR)

AF:

0.461

AC:

13070

AN:

28356

American (AMR)

AF:

0.306

AC:

13590

AN:

44366

Ashkenazi Jewish (ASJ)

AF:

0.321

AC:

7841

AN:

24458

East Asian (EAS)

AF:

0.287

AC:

11072

AN:

38548

South Asian (SAS)

AF:

0.347

AC:

28002

AN:

80650

European-Finnish (FIN)

AF:

0.290

AC:

15376

AN:

53078

Middle Eastern (MID)

AF:

0.321

AC:

1360

AN:

4242

European-Non Finnish (NFE)

AF:

0.324

AC:

286253

AN:

884140

Other (OTH)

AF:

0.330

AC:

17142

AN:

51876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

14258

28516

42775

57033

71291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8570

17140

25710

34280

42850

<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:

0.353

AC:

53689

AN:

152094

Hom.:

9821

Cov.:

AF XY:

0.350

AC XY:

26032

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.454

AC:

18838

AN:

41474

American (AMR)

AF:

0.324

AC:

4952

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

1121

AN:

3472

East Asian (EAS)

AF:

0.266

AC:

1376

AN:

5166

South Asian (SAS)

AF:

0.324

AC:

1562

AN:

4814

European-Finnish (FIN)

AF:

0.292

AC:

3092

AN:

10576

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.318

AC:

21652

AN:

67982

Other (OTH)

AF:

0.336

AC:

711

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1800

3600

5400

7200

9000

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

520

1040

1560

2080

2600

<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:

0.323

Hom.:

14711

Bravo

AF:

0.358

Asia WGS

AF:

0.282

AC:

979

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 08, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.22

(source)

DANN

Benign

0.35

PhyloP100

-0.79

Mutation Taster

=100/0

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