rs11554266

Variant names:

• chr20-58903791-C-G
• rs11554266
• NM_016592.5:c.*338C>G

Your query was ambiguous. Multiple possible variants found:

• chr20-58903791-C-G
• chr20-58903791-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000516.7(GNAS):​c.432C>G​(p.Pro144Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P144P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GNAS NM_000516.7 splice_region, synonymous
• Scores: Splicing: ADA: 0.00008431
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.333

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP7: Synonymous conserved (PhyloP=-0.333 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_016592.5	c.*338C>G		splice_region_variant	Exon 5 of 13	ENST00000371075.7	NP_057676.1
GNAS	NM_000516.7	c.432C>G	p.Pro144Pro	splice_region_variant, synonymous_variant	Exon 5 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*338C>G		3_prime_UTR_variant	Exon 5 of 12	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371075.7	c.*338C>G		splice_region_variant	Exon 5 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*293C>G		splice_region_variant	Exon 4 of 12	5		ENSP00000392000.2
GNAS	ENST00000371085.8	c.432C>G	p.Pro144Pro	splice_region_variant, synonymous_variant	Exon 5 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2364C>G	p.Pro788Pro	splice_region_variant, synonymous_variant	Exon 5 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2319C>G	p.Pro773Pro	splice_region_variant, synonymous_variant	Exon 4 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.435C>G	p.Pro145Pro	splice_region_variant, synonymous_variant	Exon 5 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.390C>G	p.Pro130Pro	splice_region_variant, synonymous_variant	Exon 4 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.258C>G	p.Pro86Pro	splice_region_variant, synonymous_variant	Exon 5 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.258C>G	p.Pro86Pro	splice_region_variant, synonymous_variant	Exon 6 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.258C>G	p.Pro86Pro	splice_region_variant, synonymous_variant	Exon 5 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.213C>G	p.Pro71Pro	splice_region_variant, synonymous_variant	Exon 4 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.213C>G	p.Pro71Pro	splice_region_variant, synonymous_variant	Exon 5 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.213C>G	p.Pro71Pro	splice_region_variant, synonymous_variant	Exon 4 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.213C>G	p.Pro71Pro	splice_region_variant, synonymous_variant	Exon 4 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.213C>G	p.Pro71Pro	splice_region_variant, synonymous_variant	Exon 4 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.213C>G	p.Pro71Pro	splice_region_variant, synonymous_variant	Exon 4 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.213C>G	p.Pro71Pro	splice_region_variant, synonymous_variant	Exon 4 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075	c.*338C>G		3_prime_UTR_variant	Exon 5 of 12	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292	c.*293C>G		3_prime_UTR_variant	Exon 4 of 11	5		ENSP00000392000.2
GNAS	ENST00000461152.6	c.*388C>G		downstream_gene_variant		5		ENSP00000499274.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152084 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251494 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461814 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727212

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: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152084 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74298

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.4
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000084
dbscSNV1_RF	Benign	0.16
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

Publications

LitVar

Other links and lift over

dbSNP: rs11554266; hg19: chr20-57478846;