rs760146185

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_000516.7(GNAS):c.138G>A(p.Leu46Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000377 in 1,060,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L46L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 0.0000038 ( 0 hom. )

Consequence

GNAS
NM_000516.7 splice_region, synonymous

Scores

Splicing: ADA: 0.0006679

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 2.61

Publications

0 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: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP7

Synonymous conserved (PhyloP=2.61 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7 link	c.138G>A	p.Leu46Leu	splice_region_variant, synonymous_variant	Exon 1 of 13	ENST00000371085.8	NP_000507.1	P63092-1O95467A0A0S2Z3H8
GNAS	NM_016592.5 link	c.*43-3748G>A		intron_variant	Intron 1 of 12	ENST00000371075.7	NP_057676.1	O95467-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GNAS	ENST00000371085.8 link	c.138G>A	p.Leu46Leu	splice_region_variant, synonymous_variant	Exon 1 of 13	1	NM_000516.7	ENSP00000360126.3	P63092-1
GNAS	ENST00000354359.12 link	c.138G>A	p.Leu46Leu	splice_region_variant, synonymous_variant	Exon 1 of 13	1		ENSP00000346328.7	P63092-4
GNAS	ENST00000371095.7 link	c.138G>A	p.Leu46Leu	splice_region_variant, synonymous_variant	Exon 1 of 12	1		ENSP00000360136.3	P63092-2
GNAS	ENST00000371075.7 link	c.*43-3748G>A		intron_variant	Intron 1 of 12	1	NM_016592.5	ENSP00000360115.3	O95467-1
GNAS	ENST00000676826.2 link	c.2069-3748G>A		intron_variant	Intron 1 of 12			ENSP00000504675.2	A0A7I2V5R6
GNAS	ENST00000371102.8 link	c.2069-3748G>A		intron_variant	Intron 1 of 11	5		ENSP00000360143.4	Q5JWF2-2
GNAS	ENST00000470512.6 link	c.-39+2511G>A		intron_variant	Intron 1 of 12	5		ENSP00000499552.2	A0A590UJQ9
GNAS	ENST00000480232.6 link	c.-39+2315G>A		intron_variant	Intron 2 of 13	5		ENSP00000499545.2	A0A590UJQ9
GNAS	ENST00000663479.2 link	c.-38-3748G>A		intron_variant	Intron 1 of 12			ENSP00000499353.2	A0A590UJQ9
GNAS	ENST00000462499.6 link	c.-38-3748G>A		intron_variant	Intron 1 of 11	2		ENSP00000499758.2	A0A590UK28
GNAS	ENST00000467227.6 link	c.-38-3748G>A		intron_variant	Intron 2 of 12	3		ENSP00000499681.2	A0A590UK28
GNAS	ENST00000478585.6 link	c.-39+2511G>A		intron_variant	Intron 1 of 11	2		ENSP00000499762.2	A0A590UK28
GNAS	ENST00000481039.6 link	c.-39+2956G>A		intron_variant	Intron 1 of 11	5		ENSP00000499767.2	A0A590UK28
GNAS	ENST00000485673.6 link	c.-39+2315G>A		intron_variant	Intron 1 of 11	5		ENSP00000499334.2	A0A590UK28
GNAS	ENST00000488546.6 link	c.-39+3046G>A		intron_variant	Intron 1 of 11	5		ENSP00000499332.2	A0A590UK28
GNAS	ENST00000461152.6 link	c.*51+1075G>A		intron_variant	Intron 1 of 2	5		ENSP00000499274.1	A0A590UJ46
GNAS	ENST00000453292.7 link	c.*43-3748G>A		intron_variant	Intron 1 of 11	5		ENSP00000392000.2	O95467-1A2A2S1
GNAS	ENST00000492907.6 link	c.-384G>A		upstream_gene_variant		3		ENSP00000499443.2	A0A590UK28

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000553

AC:

AN:

180912

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000121

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000377

AC:

AN:

1060800

Hom.:

Cov.:

AF XY:

0.00000383

AC XY:

AN XY:

521512

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21216

American (AMR)

AF:

0.00

AC:

AN:

27496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13088

East Asian (EAS)

AF:

0.00

AC:

AN:

8942

South Asian (SAS)

AF:

0.00

AC:

AN:

58788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2614

European-Non Finnish (NFE)

AF:

0.00000460

AC:

AN:

868688

Other (OTH)

AF:

0.00

AC:

AN:

35922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 14, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GNAS-related disorder

Benign:1

Sep 07, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

2.6

PromoterAI

0.0062

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00067

dbscSNV1_RF

Benign

0.0040

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over