20-58906093-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_080425.4(GNAS):c.2459+613A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,168 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 ( 0 hom., cov: 32)

Consequence

GNAS
NM_080425.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.166

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
GNAS	NM_080425.4 link	c.2459+613A>T	intron_variant	Intron 6 of 12	ENST00000371100.9	NP_536350.2
GNAS	NM_000516.7 link	c.530+613A>T	intron_variant	Intron 6 of 12	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5 link	c.*436+613A>T	intron_variant	Intron 6 of 12	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
GNAS	ENST00000371100.9 link	c.2459+613A>T	intron_variant	Intron 6 of 12	5	NM_080425.4	ENSP00000360141.3
GNAS	ENST00000371085.8 link	c.530+613A>T	intron_variant	Intron 6 of 12	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000371075.7 link	c.*436+613A>T	intron_variant	Intron 6 of 12	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2 link	c.2462+613A>T	intron_variant	Intron 6 of 12			ENSP00000504675.2
GNAS	ENST00000371102.8 link	c.2417+613A>T	intron_variant	Intron 5 of 11	5		ENSP00000360143.4
GNAS	ENST00000354359.12 link	c.533+613A>T	intron_variant	Intron 6 of 12	1		ENSP00000346328.7
GNAS	ENST00000371095.7 link	c.488+613A>T	intron_variant	Intron 5 of 11	1		ENSP00000360136.3
GNAS	ENST00000470512.6 link	c.356+613A>T	intron_variant	Intron 6 of 12	5		ENSP00000499552.2
GNAS	ENST00000480232.6 link	c.356+613A>T	intron_variant	Intron 7 of 13	5		ENSP00000499545.2
GNAS	ENST00000663479.2 link	c.356+613A>T	intron_variant	Intron 6 of 12			ENSP00000499353.2
GNAS	ENST00000462499.6 link	c.311+613A>T	intron_variant	Intron 5 of 11	2		ENSP00000499758.2
GNAS	ENST00000467227.6 link	c.311+613A>T	intron_variant	Intron 6 of 12	3		ENSP00000499681.2
GNAS	ENST00000478585.6 link	c.311+613A>T	intron_variant	Intron 5 of 11	2		ENSP00000499762.2
GNAS	ENST00000481039.6 link	c.311+613A>T	intron_variant	Intron 5 of 11	5		ENSP00000499767.2
GNAS	ENST00000485673.6 link	c.311+613A>T	intron_variant	Intron 5 of 11	5		ENSP00000499334.2
GNAS	ENST00000488546.6 link	c.311+613A>T	intron_variant	Intron 5 of 11	5		ENSP00000499332.2
GNAS	ENST00000492907.6 link	c.311+613A>T	intron_variant	Intron 5 of 11	3		ENSP00000499443.2
GNAS	ENST00000453292.7 link	c.*391+613A>T	intron_variant	Intron 5 of 11	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41522

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

9.2

(source)

DANN

Benign

0.87

PhyloP100

-0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over