rs6123837

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The ENST00000461152.6(GNAS):c.636G>A(p.Ser212Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 152,126 control chromosomes in the GnomAD database, including 9,353 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 0.31 ( 9329 hom., cov: 32)

Exomes 𝑓: 0.43 ( 24 hom. )

Consequence

GNAS
ENST00000461152.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.15

Publications

21 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP7

Synonymous conserved (PhyloP=1.15 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_080425.4 link	c.2069-5096G>A		intron_variant	Intron 1 of 12	ENST00000371100.9	NP_536350.2
GNAS	NM_016592.5 link	c.*43-5096G>A		intron_variant	Intron 1 of 12	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GNAS	ENST00000461152.6 link	c.636G>A	p.Ser212Ser	synonymous_variant	Exon 1 of 3	5		ENSP00000499274.1
GNAS	ENST00000371100.9 link	c.2069-5096G>A		intron_variant	Intron 1 of 12	5	NM_080425.4	ENSP00000360141.3
GNAS	ENST00000371075.7 link	c.*43-5096G>A		intron_variant	Intron 1 of 12	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2 link	c.2069-5096G>A		intron_variant	Intron 1 of 12			ENSP00000504675.2
GNAS	ENST00000371102.8 link	c.2069-5096G>A		intron_variant	Intron 1 of 11	5		ENSP00000360143.4
GNAS	ENST00000470512.6 link	c.-39+1163G>A		intron_variant	Intron 1 of 12	5		ENSP00000499552.2
GNAS	ENST00000480232.6 link	c.-39+967G>A		intron_variant	Intron 2 of 13	5		ENSP00000499545.2
GNAS	ENST00000663479.2 link	c.-38-5096G>A		intron_variant	Intron 1 of 12			ENSP00000499353.2
GNAS	ENST00000462499.6 link	c.-38-5096G>A		intron_variant	Intron 1 of 11	2		ENSP00000499758.2
GNAS	ENST00000467227.6 link	c.-38-5096G>A		intron_variant	Intron 2 of 12	3		ENSP00000499681.2
GNAS	ENST00000478585.6 link	c.-39+1163G>A		intron_variant	Intron 1 of 11	2		ENSP00000499762.2
GNAS	ENST00000481039.6 link	c.-39+1608G>A		intron_variant	Intron 1 of 11	5		ENSP00000499767.2
GNAS	ENST00000485673.6 link	c.-39+967G>A		intron_variant	Intron 1 of 11	5		ENSP00000499334.2
GNAS	ENST00000488546.6 link	c.-39+1698G>A		intron_variant	Intron 1 of 11	5		ENSP00000499332.2
GNAS	ENST00000453292.7 link	c.*43-5096G>A		intron_variant	Intron 1 of 11	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes

AF:

0.311

AC:

47218

AN:

151782

Hom.:

9334

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0826

Gnomad AMI

AF:

0.466

Gnomad AMR

AF:

0.429

Gnomad ASJ

AF:

0.432

Gnomad EAS

AF:

0.672

Gnomad SAS

AF:

0.602

Gnomad FIN

AF:

0.359

Gnomad MID

AF:

0.392

Gnomad NFE

AF:

0.359

Gnomad OTH

AF:

0.339

GnomAD4 exome

AF:

0.432

AC:

102

AN:

236

Hom.:

AF XY:

0.443

AC XY:

AN XY:

176

show subpopulations

African (AFR)

AF:

0.167

AC:

AN:

American (AMR)

AF:

1.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.333

AC:

AN:

East Asian (EAS)

AF:

1.00

AC:

AN:

South Asian (SAS)

AF:

1.00

AC:

AN:

European-Finnish (FIN)

AF:

0.667

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.412

AC:

AN:

204

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.311

AC:

47205

AN:

151890

Hom.:

9329

Cov.:

AF XY:

0.321

AC XY:

23785

AN XY:

74204

show subpopulations

African (AFR)

AF:

0.0823

AC:

3419

AN:

41526

American (AMR)

AF:

0.429

AC:

6562

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.432

AC:

1501

AN:

3472

East Asian (EAS)

AF:

0.672

AC:

3402

AN:

5060

South Asian (SAS)

AF:

0.601

AC:

2898

AN:

4820

European-Finnish (FIN)

AF:

0.359

AC:

3798

AN:

10568

Middle Eastern (MID)

AF:

0.373

AC:

109

AN:

292

European-Non Finnish (NFE)

AF:

0.359

AC:

24380

AN:

67850

Other (OTH)

AF:

0.337

AC:

712

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1515

3029

4544

6058

7573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

476

952

1428

1904

2380

<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:

0.334

Hom.:

11422

Bravo

AF:

0.307

Asia WGS

AF:

0.584

AC:

2020

AN:

3460

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over