rs121913494

Variant names:

• chr20-58909541-A-C
• rs121913494
• NM_000516.7:c.680A>C

Your query was ambiguous. Multiple possible variants found:

• chr20-58909541-A-C
• chr20-58909541-A-G
• chr20-58909541-A-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000516.7(GNAS):​c.680A>C​(p.Gln227Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 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. Q227H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.83
• 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr20-58909542-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 15936.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.680A>C	p.Gln227Pro	missense_variant	Exon 9 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*586A>C		3_prime_UTR_variant	Exon 9 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.680A>C	p.Gln227Pro	missense_variant	Exon 9 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2612A>C	p.Gln871Pro	missense_variant	Exon 9 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2567A>C	p.Gln856Pro	missense_variant	Exon 8 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.683A>C	p.Gln228Pro	missense_variant	Exon 9 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.638A>C	p.Gln213Pro	missense_variant	Exon 8 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.506A>C	p.Gln169Pro	missense_variant	Exon 9 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.506A>C	p.Gln169Pro	missense_variant	Exon 10 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.506A>C	p.Gln169Pro	missense_variant	Exon 9 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.461A>C	p.Gln154Pro	missense_variant	Exon 8 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.461A>C	p.Gln154Pro	missense_variant	Exon 9 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.461A>C	p.Gln154Pro	missense_variant	Exon 8 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.461A>C	p.Gln154Pro	missense_variant	Exon 8 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.461A>C	p.Gln154Pro	missense_variant	Exon 8 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.461A>C	p.Gln154Pro	missense_variant	Exon 8 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.461A>C	p.Gln154Pro	missense_variant	Exon 8 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*586A>C		3_prime_UTR_variant	Exon 9 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*541A>C		3_prime_UTR_variant	Exon 8 of 12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

⚠️ 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: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;.;.;D;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T;T;T;T;T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.6	.;.;.;H;.;.
PhyloP100		8.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;.;D
Vest4		0.95
MutPred		0.82		Loss of catalytic residue at Q870 (P = 0.0214);.;.;.;.;.;
MVP		1.0
MPC		3.4
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		1.0
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121913494; hg19: chr20-57484596;