20-58903393-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The ENST00000475610.2(GNAS):n.626A>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 791,184 control chromosomes in the GnomAD database, including 31,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 7086 hom., cov: 31)

Exomes 𝑓: 0.26 ( 23971 hom. )

Consequence

GNAS
ENST00000475610.2 non_coding_transcript_exon

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.488

Publications

10 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 20-58903393-A-T is Benign according to our data. Variant chr20-58903393-A-T is described in ClinVar as Benign. ClinVar VariationId is 1247589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7 link	c.258-138A>T		intron_variant	Intron 3 of 12	ENST00000371085.8	NP_000507.1	P63092-1O95467A0A0S2Z3H8
GNAS	NM_016592.5 link	c.*161-135A>T		intron_variant	Intron 3 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.258-138A>T	intron_variant	Intron 3 of 12	1	NM_000516.7	ENSP00000360126.3	P63092-1
GNAS	ENST00000371075.7 link	c.*161-135A>T	intron_variant	Intron 3 of 12	1	NM_016592.5	ENSP00000360115.3	O95467-1
GNAS	ENST00000676826.2 link	c.2187-135A>T	intron_variant	Intron 3 of 12			ENSP00000504675.2	A0A7I2V5R6
GNAS	ENST00000371102.8 link	c.2142-135A>T	intron_variant	Intron 2 of 11	5		ENSP00000360143.4	Q5JWF2-2
GNAS	ENST00000354359.12 link	c.258-135A>T	intron_variant	Intron 3 of 12	1		ENSP00000346328.7	P63092-4
GNAS	ENST00000371095.7 link	c.213-135A>T	intron_variant	Intron 2 of 11	1		ENSP00000360136.3	P63092-2
GNAS	ENST00000470512.6 link	c.81-135A>T	intron_variant	Intron 3 of 12	5		ENSP00000499552.2	A0A590UJQ9
GNAS	ENST00000480232.6 link	c.81-135A>T	intron_variant	Intron 4 of 13	5		ENSP00000499545.2	A0A590UJQ9
GNAS	ENST00000663479.2 link	c.81-135A>T	intron_variant	Intron 3 of 12			ENSP00000499353.2	A0A590UJQ9
GNAS	ENST00000462499.6 link	c.36-135A>T	intron_variant	Intron 2 of 11	2		ENSP00000499758.2	A0A590UK28
GNAS	ENST00000467227.6 link	c.36-135A>T	intron_variant	Intron 3 of 12	3		ENSP00000499681.2	A0A590UK28
GNAS	ENST00000478585.6 link	c.36-135A>T	intron_variant	Intron 2 of 11	2		ENSP00000499762.2	A0A590UK28
GNAS	ENST00000481039.6 link	c.36-135A>T	intron_variant	Intron 2 of 11	5		ENSP00000499767.2	A0A590UK28
GNAS	ENST00000485673.6 link	c.36-135A>T	intron_variant	Intron 2 of 11	5		ENSP00000499334.2	A0A590UK28
GNAS	ENST00000488546.6 link	c.36-135A>T	intron_variant	Intron 2 of 11	5		ENSP00000499332.2	A0A590UK28
GNAS	ENST00000492907.6 link	c.36-135A>T	intron_variant	Intron 2 of 11	3		ENSP00000499443.2	A0A590UK28
GNAS	ENST00000461152.6 link	c.*125-135A>T	intron_variant	Intron 2 of 2	5		ENSP00000499274.1	A0A590UJ46
GNAS	ENST00000453292.7 link	c.*116-135A>T	intron_variant	Intron 2 of 11	5		ENSP00000392000.2	O95467-1A2A2S1

Frequencies

GnomAD3 genomes

AF:

0.295

AC:

44781

AN:

152024

Hom.:

7078

Cov.:

show subpopulations

Gnomad AFR

AF:

0.372

Gnomad AMI

AF:

0.161

Gnomad AMR

AF:

0.209

Gnomad ASJ

AF:

0.289

Gnomad EAS

AF:

0.0945

Gnomad SAS

AF:

0.134

Gnomad FIN

AF:

0.342

Gnomad MID

AF:

0.279

Gnomad NFE

AF:

0.289

Gnomad OTH

AF:

0.280

GnomAD4 exome

AF:

0.261

AC:

167072

AN:

639042

Hom.:

23971

Cov.:

AF XY:

0.256

AC XY:

87276

AN XY:

340836

show subpopulations

African (AFR)

AF:

0.370

AC:

6435

AN:

17388

American (AMR)

AF:

0.151

AC:

5286

AN:

34934

Ashkenazi Jewish (ASJ)

AF:

0.292

AC:

6005

AN:

20552

East Asian (EAS)

AF:

0.118

AC:

3836

AN:

32582

South Asian (SAS)

AF:

0.132

AC:

8505

AN:

64532

European-Finnish (FIN)

AF:

0.333

AC:

12100

AN:

36294

Middle Eastern (MID)

AF:

0.264

AC:

883

AN:

3340

European-Non Finnish (NFE)

AF:

0.291

AC:

115089

AN:

396096

Other (OTH)

AF:

0.268

AC:

8933

AN:

33324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

6949

13898

20848

27797

34746

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1454

2908

4362

5816

7270

<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:

0.295

AC:

44828

AN:

152142

Hom.:

7086

Cov.:

AF XY:

0.291

AC XY:

21668

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.372

AC:

15417

AN:

41486

American (AMR)

AF:

0.208

AC:

3183

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.289

AC:

1004

AN:

3472

East Asian (EAS)

AF:

0.0940

AC:

487

AN:

5182

South Asian (SAS)

AF:

0.134

AC:

649

AN:

4828

European-Finnish (FIN)

AF:

0.342

AC:

3621

AN:

10578

Middle Eastern (MID)

AF:

0.269

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.289

AC:

19636

AN:

67990

Other (OTH)

AF:

0.287

AC:

606

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1587

3174

4762

6349

7936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

432

864

1296

1728

2160

<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:

0.201

Hom.:

504

Bravo

AF:

0.289

Asia WGS

AF:

0.182

AC:

633

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 12, 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

-0.45

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

0.49

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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