20-58885457-T-C

Variant names:

• chr20-58885457-T-C
• rs62203846
• NM_080425.4:c.2069-10155T>C

Variant summary

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

The ENST00000371075.7(GNAS):​c.*43-10155T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 152,250 control chromosomes in the GnomAD database, including 1,656 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 0.13 (1656 hom., cov: 33)
• Consequence: GNAS ENST00000371075.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.191
• Publications: 1 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

ENSG00000225806 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000371075.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	NM_080425.4	MANE Plus Clinical	c.2069-10155T>C		intron	N/A	NP_536350.2
	GNAS	NM_016592.5	MANE Plus Clinical	c.*43-10155T>C		intron	N/A	NP_057676.1
	GNAS	NM_001410913.1		c.2069-10155T>C		intron	N/A	NP_001397842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.2069-10155T>C		intron	N/A	ENSP00000360141.3
	GNAS	ENST00000371075.7	TSL:1 MANE Plus Clinical	c.*43-10155T>C		intron	N/A	ENSP00000360115.3
	GNAS	ENST00000676826.2		c.2069-10155T>C		intron	N/A	ENSP00000504675.2

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19433 AN: 152132 Hom.: 1657 Cov.: 33

Gnomad AFR AF: 0.0462

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0466

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.126

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

GnomAD4 genome AF: 0.128 AC: 19421 AN: 152250 Hom.: 1656 Cov.: 33 AF XY: 0.127 AC XY: 9456 AN XY: 74434

African (AFR) AF: 0.0461 AC: 1914 AN: 41558

American (AMR) AF: 0.104 AC: 1584 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 487 AN: 3472

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.0462 AC: 223 AN: 4826

European-Finnish (FIN) AF: 0.242 AC: 2556 AN: 10578

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12222 AN: 68016

Other (OTH) AF: 0.125 AC: 264 AN: 2114

Alfa AF: 0.157 Hom.: 291

Bravo AF: 0.116

Asia WGS AF: 0.0270 AC: 93 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.3
DANN	Benign	0.77
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs62203846; hg19: chr20-57460512;