chr20-58909542-G-T

Variant names:

• chr20-58909542-G-T
• rs137854533
• NM_000516.7:c.681G>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000516.7(GNAS):​c.681G>T​(p.Gln227His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 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 not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q227?) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.15

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a region_of_interest G3 motif (size 9) in uniprot entity GNAS2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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-Y is described in Lovd as [Pathogenic].
• PP2: Missense variant in the GNAS gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 58 curated pathogenic missense variants (we use a threshold of 10). The gene has 64 curated benign missense variants. Gene score misZ: 2.6546 (below the threshold of 3.09). Trascript score misZ: 4.8361 (above the threshold of 3.09). GenCC associations: The gene is linked to ACTH-independent macronodular adrenal hyperplasia 1, pseudohypoparathyroidism type 1B, pseudohypoparathyroidism type 1C, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia, pseudopseudohypoparathyroidism, McCune-Albright syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.681G>T	p.Gln227His	missense_variant	Exon 9 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*587G>T		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.681G>T	p.Gln227His	missense_variant	Exon 9 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2613G>T	p.Gln871His	missense_variant	Exon 9 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2568G>T	p.Gln856His	missense_variant	Exon 8 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.684G>T	p.Gln228His	missense_variant	Exon 9 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.639G>T	p.Gln213His	missense_variant	Exon 8 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.507G>T	p.Gln169His	missense_variant	Exon 9 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.507G>T	p.Gln169His	missense_variant	Exon 10 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.507G>T	p.Gln169His	missense_variant	Exon 9 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.462G>T	p.Gln154His	missense_variant	Exon 8 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.462G>T	p.Gln154His	missense_variant	Exon 9 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.462G>T	p.Gln154His	missense_variant	Exon 8 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.462G>T	p.Gln154His	missense_variant	Exon 8 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.462G>T	p.Gln154His	missense_variant	Exon 8 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.462G>T	p.Gln154His	missense_variant	Exon 8 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.462G>T	p.Gln154His	missense_variant	Exon 8 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*587G>T		3_prime_UTR_variant	Exon 9 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*542G>T		3_prime_UTR_variant	Exon 8 of 12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

McCune-Albright syndrome Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.;.;D;.;.
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	4.3	.;.;.;H;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.5	D;D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;.;D
Vest4		0.93
MutPred		0.80		Gain of disorder (P = 0.2045);.;.;.;.;.;
MVP		0.98
MPC		3.0
ClinPred		1.0	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137854533; hg19: chr20-57484597; COSMIC: COSV55673870; COSMIC: COSV55673870;