20-58888938-C-T

Variant names:

• chr20-58888938-C-T
• rs6026579
• NM_080425.4:c.2069-6674C>T

Variant summary

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

The NM_080425.4(GNAS):​c.2069-6674C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 274,276 control chromosomes in the GnomAD database, including 61,217 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 0.67 (33224 hom., cov: 31)
  • Exomes 𝑓: 0.67 (27993 hom.)
• Consequence: GNAS NM_080425.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• 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

ENSG00000225806 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.736 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080425.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	NM_080425.4	MANE Plus Clinical	c.2069-6674C>T		intron	N/A	NP_536350.2
	GNAS	NM_016592.5	MANE Plus Clinical	c.*43-6674C>T		intron	N/A	NP_057676.1
	GNAS	NM_001410913.1		c.2069-6674C>T		intron	N/A	NP_001397842.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.2069-6674C>T		intron	N/A	ENSP00000360141.3
	GNAS	ENST00000371075.7	TSL:1 MANE Plus Clinical	c.*43-6674C>T		intron	N/A	ENSP00000360115.3
	GNAS	ENST00000676826.2		c.2069-6674C>T		intron	N/A	ENSP00000504675.2

Frequencies

GnomAD3 genomes AF: 0.665 AC: 99362 AN: 149346 Hom.: 33194 Cov.: 31

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.665

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.691

Gnomad EAS AF: 0.748

Gnomad SAS AF: 0.757

Gnomad FIN AF: 0.687

Gnomad MID AF: 0.678

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.677

GnomAD4 exome AF: 0.667 AC: 83245 AN: 124826 Hom.: 27993 Cov.: 4 AF XY: 0.668 AC XY: 39613 AN XY: 59296

African (AFR) AF: 0.630 AC: 1474 AN: 2340

American (AMR) AF: 0.734 AC: 113 AN: 154

Ashkenazi Jewish (ASJ) AF: 0.749 AC: 559 AN: 746

East Asian (EAS) AF: 0.758 AC: 405 AN: 534

South Asian (SAS) AF: 0.745 AC: 1848 AN: 2480

European-Finnish (FIN) AF: 0.700 AC: 28 AN: 40

Middle Eastern (MID) AF: 0.724 AC: 178 AN: 246

European-Non Finnish (NFE) AF: 0.664 AC: 75809 AN: 114140

Other (OTH) AF: 0.683 AC: 2831 AN: 4146

GnomAD4 genome AF: 0.665 AC: 99431 AN: 149450 Hom.: 33224 Cov.: 31 AF XY: 0.669 AC XY: 48799 AN XY: 72954

African (AFR) AF: 0.635 AC: 26122 AN: 41164

American (AMR) AF: 0.679 AC: 10212 AN: 15036

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 2370 AN: 3430

East Asian (EAS) AF: 0.748 AC: 3810 AN: 5094

South Asian (SAS) AF: 0.757 AC: 3656 AN: 4830

European-Finnish (FIN) AF: 0.687 AC: 6637 AN: 9660

Middle Eastern (MID) AF: 0.661 AC: 193 AN: 292

European-Non Finnish (NFE) AF: 0.663 AC: 44415 AN: 66960

Other (OTH) AF: 0.680 AC: 1412 AN: 2076

Alfa AF: 0.655 Hom.: 10486

Bravo AF: 0.665

Asia WGS AF: 0.753 AC: 2570 AN: 3412

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.0
DANN	Benign	0.96
PhyloP100		-1.2
PromoterAI		0.013	Neutral
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: rs6026579; hg19: chr20-57463993;