rs587778382

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBS1BS2

The ENST00000676826.2(GNAS):c.1233_1259delCGACTCCGGGACAGCACCAGCCGATCC(p.Asp412_Pro420del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000846 in 1,578,852 control chromosomes in the GnomAD database, including 7 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00058 ( 3 hom. )

Consequence

GNAS
ENST00000676826.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 3.02

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 links:

GNAS-AS1 (HGNC:24872): (GNAS antisense RNA 1) This gene produces a paternally-imprinted antisense RNA transcript that helps regulate the GNAS complex locus, which encodes the alpha subunit of the stimulatory G protein. Defects in this gene are a cause of pseudohypoparathyroidism type Ib.[provided by RefSeq, Jun 2010]

GNAS-AS1 Gene-Disease associations (from GenCC):

pseudohypoparathyroidism type 1B
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

GNAS-AS1 links:

ENSG00000293655 (HGNC:):

ENSG00000293655 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in ENST00000676826.2.

BP6

Variant 20-58854492-AGATCCCGACTCCGGGACAGCACCAGCC-A is Benign according to our data. Variant chr20-58854492-AGATCCCGACTCCGGGACAGCACCAGCC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00343 (509/148214) while in subpopulation AFR AF = 0.0109 (437/40036). AF 95% confidence interval is 0.0101. There are 4 homozygotes in GnomAd4. There are 252 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 509 AD,Mitochondrial,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_016592.5 link	c.42+13612_42+13638delCGACTCCGGGACAGCACCAGCCGATCC		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	ENST00000676826.2 link	c.1233_1259delCGACTCCGGGACAGCACCAGCCGATCC	p.Asp412_Pro420del	disruptive_inframe_deletion	Exon 1 of 13			ENSP00000504675.2	A0A7I2V5R6
GNAS	ENST00000371102.8 link	c.1233_1259delCGACTCCGGGACAGCACCAGCCGATCC	p.Asp412_Pro420del	disruptive_inframe_deletion	Exon 1 of 12	5		ENSP00000360143.4	Q5JWF2-2
GNAS	ENST00000371075.7 link	c.42+13612_42+13638delCGACTCCGGGACAGCACCAGCCGATCC		intron_variant	Intron 1 of 12	1	NM_016592.5	ENSP00000360115.3	O95467-1
GNAS	ENST00000663479.2 link	c.-39+12623_-39+12649delCGACTCCGGGACAGCACCAGCCGATCC		intron_variant	Intron 1 of 12			ENSP00000499353.2	A0A590UJQ9
GNAS	ENST00000462499.6 link	c.-39+12623_-39+12649delCGACTCCGGGACAGCACCAGCCGATCC		intron_variant	Intron 1 of 11	2		ENSP00000499758.2	A0A590UK28
GNAS	ENST00000467227.6 link	c.-39+10424_-39+10450delCGACTCCGGGACAGCACCAGCCGATCC		intron_variant	Intron 2 of 12	3		ENSP00000499681.2	A0A590UK28
GNAS	ENST00000453292.7 link	c.42+13612_42+13638delCGACTCCGGGACAGCACCAGCCGATCC		intron_variant	Intron 1 of 11	5		ENSP00000392000.2	O95467-1A2A2S1

Frequencies

GnomAD3 genomes

AF:

0.00346

AC:

512

AN:

148102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00193

Gnomad ASJ

AF:

0.000585

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000864

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0261

Gnomad NFE

AF:

0.000435

Gnomad OTH

AF:

0.000980

GnomAD2 exomes

AF:

0.000826

AC:

159

AN:

192610

AF XY:

0.000732

show subpopulations

Gnomad AFR exome

AF:

0.00726

Gnomad AMR exome

AF:

0.00143

Gnomad ASJ exome

AF:

0.000552

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.000984

GnomAD4 exome

AF:

0.000578

AC:

827

AN:

1430638

Hom.:

AF XY:

0.000532

AC XY:

378

AN XY:

709992

show subpopulations

African (AFR)

AF:

0.0115

AC:

374

AN:

32438

American (AMR)

AF:

0.00176

AC:

AN:

41378

Ashkenazi Jewish (ASJ)

AF:

0.000233

AC:

AN:

25778

East Asian (EAS)

AF:

0.00

AC:

AN:

37624

South Asian (SAS)

AF:

0.000363

AC:

AN:

82724

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44694

Middle Eastern (MID)

AF:

0.00488

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.000205

AC:

226

AN:

1100918

Other (OTH)

AF:

0.00152

AC:

AN:

59350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.418

Heterozygous variant carriers

108

163

217

271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00343

AC:

509

AN:

148214

Hom.:

Cov.:

AF XY:

0.00348

AC XY:

252

AN XY:

72436

show subpopulations

African (AFR)

AF:

0.0109

AC:

437

AN:

40036

American (AMR)

AF:

0.00193

AC:

AN:

15020

Ashkenazi Jewish (ASJ)

AF:

0.000585

AC:

AN:

3418

East Asian (EAS)

AF:

0.00

AC:

AN:

4944

South Asian (SAS)

AF:

0.00108

AC:

AN:

4632

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10300

Middle Eastern (MID)

AF:

0.0175

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000435

AC:

AN:

66666

Other (OTH)

AF:

0.000971

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00221

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GNAS: PM4, BS1, BS2 -

GNAS-related disorder

Benign:1

Jun 13, 2019

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). -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.0

Mutation Taster

=196/4

polymorphism

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over