rs137854530

Variant names:

• chr20-58891727-A-G
• rs137854530
• NM_000516.7:c.1A>G

Your query was ambiguous. Multiple possible variants found:

• chr20-58891727-A-G
• chr20-58891727-A-T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000516.7(GNAS):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000996 in 1,004,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: GNAS NM_000516.7 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.80
• Publications: 7 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 38 pathogenic variants. Next in-frame start position is after 60 codons. Genomic position: 58895650. Lost 0.150 part of the original CDS.
• PS1: Another start lost variant in NM_000516.7 (GNAS) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-58891727-A-G is Pathogenic according to our data. Variant chr20-58891727-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 15927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.1A>G	p.Met1?	start_lost	Exon 1 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*43-3885A>G		intron_variant	Intron 1 of 12	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.1A>G	p.Met1?	start_lost	Exon 1 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000354359.12	c.1A>G	p.Met1?	start_lost	Exon 1 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	1		ENSP00000360136.3
GNAS	ENST00000371075.7	c.*43-3885A>G		intron_variant	Intron 1 of 12	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2069-3885A>G		intron_variant	Intron 1 of 12			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2069-3885A>G		intron_variant	Intron 1 of 11	5		ENSP00000360143.4
GNAS	ENST00000470512.6	c.-39+2374A>G		intron_variant	Intron 1 of 12	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.-39+2178A>G		intron_variant	Intron 2 of 13	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.-38-3885A>G		intron_variant	Intron 1 of 12			ENSP00000499353.2
GNAS	ENST00000462499.6	c.-38-3885A>G		intron_variant	Intron 1 of 11	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.-38-3885A>G		intron_variant	Intron 2 of 12	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.-39+2374A>G		intron_variant	Intron 1 of 11	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.-39+2819A>G		intron_variant	Intron 1 of 11	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.-39+2178A>G		intron_variant	Intron 1 of 11	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.-39+2909A>G		intron_variant	Intron 1 of 11	5		ENSP00000499332.2
GNAS	ENST00000461152.6	c.*51+938A>G		intron_variant	Intron 1 of 2	5		ENSP00000499274.1
GNAS	ENST00000453292.7	c.*43-3885A>G		intron_variant	Intron 1 of 11	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 9.96e-7 AC: 1 AN: 1004328 Hom.: 0 Cov.: 32 AF XY: 0.00000206 AC XY: 1 AN XY: 486476

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20428

American (AMR) AF: 0.00 AC: 0 AN: 24594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12254

East Asian (EAS) AF: 0.00 AC: 0 AN: 8256

South Asian (SAS) AF: 0.00 AC: 0 AN: 42788

European-Finnish (FIN) AF: 0.0000495 AC: 1 AN: 20218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2430

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839692

Other (OTH) AF: 0.00 AC: 0 AN: 33668

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Nov 20, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variants (Met1?) in GNAS likely lead to the use of an alternate initiation codon and the loss of the first 59 residues (PMID: 21713996, 2109828); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 2109828, 31546270, 27535533, 21713996, 31886927, 23533243) -

Aug 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that disruption of the initiator codon affects GNAS function (PMID: 21713996). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 15927). Disruption of the initiator codon has been observed in individual(s) with Albright’s hereditary osteodystrophy (PMID: 2109828, 21713996). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the GNAS mRNA. The next in-frame methionine is located at codon 60. -

Pseudohypoparathyroidism Pathogenic:1

May 17, 1990

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cushing syndrome;C0033806:Pseudohypoparathyroidism;C0033835:Pseudopseudohypoparathyroidism;C0242292:McCune-Albright syndrome;C0334041:Progressive osseous heteroplasia;C1864100:Pseudohypoparathyroidism type 1B;C2932716:Pseudohypoparathyroidism type 1C;C4540135:Pituitary adenoma 3, multiple types Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Uncertain	0.45	.;T;.;.;T;T
Eigen	Benign	0.10
Eigen_PC	Benign	-0.041
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
PhyloP100		6.8
PROVEAN	Benign	-2.0	N;N;N;N;D;N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		0.99, 0.99	.;D;.;D;.;.
Vest4		0.76
MutPred		0.99		Loss of catalytic residue at M1 (P = 0.155);Loss of catalytic residue at M1 (P = 0.155);Loss of catalytic residue at M1 (P = 0.155);Loss of catalytic residue at M1 (P = 0.155);Loss of catalytic residue at M1 (P = 0.155);Loss of catalytic residue at M1 (P = 0.155);
MVP		1.0
ClinPred		0.95	D
GERP RS		1.9
PromoterAI		-0.51	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs137854530; hg19: chr20-57466782;