20-58839812-C-G

Variant names:

• chr20-58839812-C-G
• rs61558260
• NM_016592.5:c.-295C>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.-295C>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 0.0379 in 585,262 control chromosomes in the GnomAD database, including 879 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (529 hom., cov: 32)
  • Exomes 𝑓: 0.030 (350 hom.)
• Consequence: GNAS NM_016592.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.886
• Publications: 7 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=-0.81).
• BP6: Variant 20-58839812-C-G is Benign according to our data. Variant chr20-58839812-C-G is described in ClinVar as Benign. ClinVar VariationId is 1282105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	NM_016592.5	MANE Plus Clinical	c.-295C>G		5_prime_UTR	Exon 1 of 13	NP_057676.1	O95467-1
	GNAS-AS1	NR_185847.1	MANE Select	n.672+2125G>C		intron	N/A
	GNAS	NM_001410912.1		c.-1032C>G		5_prime_UTR	Exon 1 of 13	NP_001397841.1	A0A0A0MR13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371075.7	TSL:1 MANE Plus Clinical	c.-295C>G		5_prime_UTR	Exon 1 of 13	ENSP00000360115.3	O95467-1
	GNAS	ENST00000313949.11	TSL:1	c.-295C>G		5_prime_UTR	Exon 1 of 13	ENSP00000323571.7	O95467-1
	GNAS-AS1	ENST00000718285.1	MANE Select	n.672+2125G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0598 AC: 9096 AN: 152180 Hom.: 520 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.0414

Gnomad FIN AF: 0.00706

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0299

Gnomad OTH AF: 0.0554

GnomAD4 exome AF: 0.0301 AC: 13037 AN: 432964 Hom.: 350 Cov.: 0 AF XY: 0.0303 AC XY: 6856 AN XY: 226562

African (AFR) AF: 0.146 AC: 1781 AN: 12162

American (AMR) AF: 0.0227 AC: 367 AN: 16196

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 189 AN: 13500

East Asian (EAS) AF: 0.00238 AC: 72 AN: 30278

South Asian (SAS) AF: 0.0416 AC: 1742 AN: 41924

European-Finnish (FIN) AF: 0.0118 AC: 346 AN: 29370

Middle Eastern (MID) AF: 0.0257 AC: 49 AN: 1910

European-Non Finnish (NFE) AF: 0.0288 AC: 7543 AN: 262272

Other (OTH) AF: 0.0374 AC: 948 AN: 25352

GnomAD4 genome AF: 0.0600 AC: 9136 AN: 152298 Hom.: 529 Cov.: 32 AF XY: 0.0572 AC XY: 4258 AN XY: 74476

African (AFR) AF: 0.147 AC: 6095 AN: 41538

American (AMR) AF: 0.0323 AC: 495 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3468

East Asian (EAS) AF: 0.00772 AC: 40 AN: 5180

South Asian (SAS) AF: 0.0418 AC: 202 AN: 4832

European-Finnish (FIN) AF: 0.00706 AC: 75 AN: 10622

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0299 AC: 2031 AN: 68030

Other (OTH) AF: 0.0653 AC: 138 AN: 2114

Alfa AF: 0.0161 Hom.: 9

Bravo AF: 0.0648

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.62
PhyloP100		0.89
PromoterAI		-0.092	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: rs61558260; hg19: chr20-57414867;