20-58840055-A-G

Variant names:

• chr20-58840055-A-G
• rs1800900
• NM_016592.5:c.-52A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016592.5(GNAS):​c.-52A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.639 in 1,596,376 control chromosomes in the GnomAD database, including 329,219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26724 hom., cov: 29)
  • Exomes 𝑓: 0.64 (302495 hom.)
• Consequence: GNAS NM_016592.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0540
• Publications: 32 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-AS1 (HGNC:24872): (GNAS antisense RNA 1) This gene produces a paternally-imprinted antisense RNA transcript that helps regulate the GNAS complex locus, which encodes the alpha subunit of the stimulatory G protein. Defects in this gene are a cause of pseudohypoparathyroidism type Ib.[provided by RefSeq, Jun 2010]

GNAS-AS1 Gene-Disease associations (from GenCC):

• pseudohypoparathyroidism type 1B

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000293655 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 20-58840055-A-G is Benign according to our data. Variant chr20-58840055-A-G is described in ClinVar as Benign. ClinVar VariationId is 1280334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016592.5. 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_016592.5	MANE Plus Clinical	c.-52A>G		5_prime_UTR	Exon 1 of 13	NP_057676.1
	GNAS-AS1	NR_185847.1	MANE Select	n.672+1882T>C		intron	N/A
	GNAS	NM_001410912.1		c.-789A>G		5_prime_UTR	Exon 1 of 13	NP_001397841.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371075.7	TSL:1 MANE Plus Clinical	c.-52A>G		5_prime_UTR	Exon 1 of 13	ENSP00000360115.3
	GNAS	ENST00000313949.11	TSL:1	c.-52A>G		5_prime_UTR	Exon 1 of 13	ENSP00000323571.7
	GNAS-AS1	ENST00000718285.1	MANE Select	n.672+1882T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88299 AN: 151000 Hom.: 26697 Cov.: 29

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.726

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.682

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.559

GnomAD4 exome AF: 0.645 AC: 931470 AN: 1445258 Hom.: 302495 Cov.: 32 AF XY: 0.645 AC XY: 464481 AN XY: 719630

African (AFR) AF: 0.423 AC: 14103 AN: 33306

American (AMR) AF: 0.674 AC: 30090 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 13227 AN: 26044

East Asian (EAS) AF: 0.777 AC: 30804 AN: 39662

South Asian (SAS) AF: 0.685 AC: 58883 AN: 86018

European-Finnish (FIN) AF: 0.690 AC: 31356 AN: 45418

Middle Eastern (MID) AF: 0.518 AC: 2672 AN: 5158

European-Non Finnish (NFE) AF: 0.645 AC: 712795 AN: 1105026

Other (OTH) AF: 0.626 AC: 37540 AN: 59980

GnomAD4 genome AF: 0.585 AC: 88376 AN: 151118 Hom.: 26724 Cov.: 29 AF XY: 0.590 AC XY: 43547 AN XY: 73852

African (AFR) AF: 0.435 AC: 17811 AN: 40972

American (AMR) AF: 0.597 AC: 9085 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 1773 AN: 3458

East Asian (EAS) AF: 0.806 AC: 4091 AN: 5078

South Asian (SAS) AF: 0.683 AC: 3264 AN: 4782

European-Finnish (FIN) AF: 0.695 AC: 7302 AN: 10500

Middle Eastern (MID) AF: 0.441 AC: 128 AN: 290

European-Non Finnish (NFE) AF: 0.635 AC: 43077 AN: 67824

Other (OTH) AF: 0.565 AC: 1187 AN: 2102

Alfa AF: 0.607 Hom.: 35119

Bravo AF: 0.570

Asia WGS AF: 0.709 AC: 2464 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Oct 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	10
DANN	Benign	0.69
PhyloP100		-0.054
PromoterAI		-0.0097	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1800900; hg19: chr20-57415110; COSMIC: COSV100005868; COSMIC: COSV100005868;