20-58903708-G-C

Variant names:

• chr20-58903708-G-C
• rs1555889031
• NM_000516.7:c.349G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000516.7(GNAS):​c.349G>C​(p.Val117Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V117M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.59
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000516.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-58903708-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445504.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.349G>C	p.Val117Leu	missense_variant	Exon 5 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*255G>C		3_prime_UTR_variant	Exon 5 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.349G>C	p.Val117Leu	missense_variant	Exon 5 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2281G>C	p.Val761Leu	missense_variant	Exon 5 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2236G>C	p.Val746Leu	missense_variant	Exon 4 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.352G>C	p.Val118Leu	missense_variant	Exon 5 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.307G>C	p.Val103Leu	missense_variant	Exon 4 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.175G>C	p.Val59Leu	missense_variant	Exon 5 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.175G>C	p.Val59Leu	missense_variant	Exon 6 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.175G>C	p.Val59Leu	missense_variant	Exon 5 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.130G>C	p.Val44Leu	missense_variant	Exon 4 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.130G>C	p.Val44Leu	missense_variant	Exon 5 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.130G>C	p.Val44Leu	missense_variant	Exon 4 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.130G>C	p.Val44Leu	missense_variant	Exon 4 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.130G>C	p.Val44Leu	missense_variant	Exon 4 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.130G>C	p.Val44Leu	missense_variant	Exon 4 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.130G>C	p.Val44Leu	missense_variant	Exon 4 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*255G>C		3_prime_UTR_variant	Exon 5 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*210G>C		3_prime_UTR_variant	Exon 4 of 12	5		ENSP00000392000.2
GNAS	ENST00000461152.6	c.*305G>C		downstream_gene_variant		5		ENSP00000499274.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461752 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727194

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111892

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;.;.;.;D;.;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.4	.;.;.;.;.;L;.;.;.
PhyloP100		7.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.6	D;D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.018	D;D;T;.;D;T;T;D;.
Sift4G	Benign	0.072	T;T;T;T;T;T;T;T;T
Polyphen		0.76	P;.;.;.;.;B;.;B;.
Vest4		0.51
MutPred		0.56		Gain of glycosylation at P759 (P = 0.1187);.;.;.;.;.;.;.;.;
MVP		1.0
MPC		1.2
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.87
Mutation Taster		=20/80	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: rs1555889031; hg19: chr20-57478763;