rs7121

Variant names:

• chr20-58903752-C-A
• rs7121
• NM_000516.7:c.393C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-58903752-C-A
• chr20-58903752-C-G
• chr20-58903752-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP7

The NM_000516.7(GNAS):​c.393C>A​(p.Ile131Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I131I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 28)
• Consequence: GNAS NM_000516.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.364
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP7: Synonymous conserved (PhyloP=-0.364 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.393C>A	p.Ile131Ile	synonymous_variant	Exon 5 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*299C>A		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.393C>A	p.Ile131Ile	synonymous_variant	Exon 5 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2325C>A	p.Ile775Ile	synonymous_variant	Exon 5 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2280C>A	p.Ile760Ile	synonymous_variant	Exon 4 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.396C>A	p.Ile132Ile	synonymous_variant	Exon 5 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.351C>A	p.Ile117Ile	synonymous_variant	Exon 4 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.219C>A	p.Ile73Ile	synonymous_variant	Exon 5 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.219C>A	p.Ile73Ile	synonymous_variant	Exon 6 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.219C>A	p.Ile73Ile	synonymous_variant	Exon 5 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.174C>A	p.Ile58Ile	synonymous_variant	Exon 4 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.174C>A	p.Ile58Ile	synonymous_variant	Exon 5 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.174C>A	p.Ile58Ile	synonymous_variant	Exon 4 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.174C>A	p.Ile58Ile	synonymous_variant	Exon 4 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.174C>A	p.Ile58Ile	synonymous_variant	Exon 4 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.174C>A	p.Ile58Ile	synonymous_variant	Exon 4 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.174C>A	p.Ile58Ile	synonymous_variant	Exon 4 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*299C>A		3_prime_UTR_variant	Exon 5 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*254C>A		3_prime_UTR_variant	Exon 4 of 12	5		ENSP00000392000.2
GNAS	ENST00000461152.6	c.*349C>A		downstream_gene_variant		5		ENSP00000499274.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	3.9
DANN	Benign	0.85
PhyloP100		-0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs7121; hg19: chr20-57478807;