rs797045046

Variant names:

• chr20-58891760-C-G
• rs797045046
• NM_000516.7:c.34C>G

Your query was ambiguous. Multiple possible variants found:

• chr20-58891760-C-G
• chr20-58891760-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000516.7(GNAS):​c.34C>G​(p.Gln12Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000898 in 1,113,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q12H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 9.0e-7 (0 hom.)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79
• Publications: 6 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2930197).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000516.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	NM_000516.7	MANE Select	c.34C>G	p.Gln12Glu	missense	Exon 1 of 13	NP_000507.1
	GNAS	NM_080425.4	MANE Plus Clinical	c.2069-3852C>G		intron	N/A	NP_536350.2
	GNAS	NM_016592.5	MANE Plus Clinical	c.*43-3852C>G		intron	N/A	NP_057676.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371085.8	TSL:1 MANE Select	c.34C>G	p.Gln12Glu	missense	Exon 1 of 13	ENSP00000360126.3
	GNAS	ENST00000354359.12	TSL:1	c.34C>G	p.Gln12Glu	missense	Exon 1 of 13	ENSP00000346328.7
	GNAS	ENST00000371095.7	TSL:1	c.34C>G	p.Gln12Glu	missense	Exon 1 of 12	ENSP00000360136.3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.00000502 AC: 1 AN: 199320 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000360

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 8.98e-7 AC: 1 AN: 1113852 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 551478

African (AFR) AF: 0.00 AC: 0 AN: 21800

American (AMR) AF: 0.0000328 AC: 1 AN: 30482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14186

East Asian (EAS) AF: 0.00 AC: 0 AN: 9892

South Asian (SAS) AF: 0.00 AC: 0 AN: 71204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3438

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 896562

Other (OTH) AF: 0.00 AC: 0 AN: 38388

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.0052	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-0.23	N
PhyloP100		1.8
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.24
Sift	Benign	0.78	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.31		Loss of MoRF binding (P = 0.0708)
MVP		0.38
ClinPred		0.064	T
GERP RS		1.9
PromoterAI		0.060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=47/53	disease causing

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: rs797045046; hg19: chr20-57466815;