20-58894172-C-G

Variant names:

• chr20-58894172-C-G
• rs15754
• NM_000516.7:c.140-1440C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000516.7(GNAS):​c.140-1440C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.701 in 152,156 control chromosomes in the GnomAD database, including 37,684 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.70 (37684 hom., cov: 33)
• Consequence: GNAS NM_000516.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.669
• Publications: 8 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.140-1440C>G		intron_variant	Intron 1 of 12	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*43-1440C>G		intron_variant	Intron 1 of 12	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.140-1440C>G		intron_variant	Intron 1 of 12	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000371075.7	c.*43-1440C>G		intron_variant	Intron 1 of 12	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2069-1440C>G		intron_variant	Intron 1 of 12			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2069-1440C>G		intron_variant	Intron 1 of 11	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.140-1440C>G		intron_variant	Intron 1 of 12	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.140-1440C>G		intron_variant	Intron 1 of 11	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.-38-1440C>G		intron_variant	Intron 1 of 12	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.-38-1440C>G		intron_variant	Intron 2 of 13	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.-38-1440C>G		intron_variant	Intron 1 of 12			ENSP00000499353.2
GNAS	ENST00000462499.6	c.-38-1440C>G		intron_variant	Intron 1 of 11	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.-38-1440C>G		intron_variant	Intron 2 of 12	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.-38-1440C>G		intron_variant	Intron 1 of 11	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.-38-1440C>G		intron_variant	Intron 1 of 11	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.-38-1440C>G		intron_variant	Intron 1 of 11	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.-38-1440C>G		intron_variant	Intron 1 of 11	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.-38-1440C>G		intron_variant	Intron 1 of 11	3		ENSP00000499443.2
GNAS	ENST00000461152.6	c.*52-1440C>G		intron_variant	Intron 1 of 2	5		ENSP00000499274.1
GNAS	ENST00000453292.7	c.*43-1440C>G		intron_variant	Intron 1 of 11	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106598 AN: 152036 Hom.: 37644 Cov.: 33

Gnomad AFR AF: 0.778

Gnomad AMI AF: 0.665

Gnomad AMR AF: 0.691

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.751

Gnomad FIN AF: 0.669

Gnomad MID AF: 0.701

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.701

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.701 AC: 106695 AN: 152156 Hom.: 37684 Cov.: 33 AF XY: 0.702 AC XY: 52239 AN XY: 74396

African (AFR) AF: 0.778 AC: 32273 AN: 41496

American (AMR) AF: 0.691 AC: 10570 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2388 AN: 3472

East Asian (EAS) AF: 0.723 AC: 3748 AN: 5186

South Asian (SAS) AF: 0.750 AC: 3617 AN: 4824

European-Finnish (FIN) AF: 0.669 AC: 7087 AN: 10588

Middle Eastern (MID) AF: 0.678 AC: 198 AN: 292

European-Non Finnish (NFE) AF: 0.658 AC: 44719 AN: 67988

Other (OTH) AF: 0.705 AC: 1490 AN: 2112

Alfa AF: 0.694 Hom.: 4552

Bravo AF: 0.708

Asia WGS AF: 0.765 AC: 2658 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.7
DANN	Benign	0.59
PhyloP100		-0.67
Mutation Taster		=100/0	polymorphism (auto)

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: rs15754; hg19: chr20-57469227;