20-58840400-C-T

Variant names:

• chr20-58840400-C-T
• rs1800902
• NM_016592.5:c.294C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001410912.1(GNAS):​c.-444C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.033 in 1,613,458 control chromosomes in the GnomAD database, including 1,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.048 (283 hom., cov: 32)
  • Exomes 𝑓: 0.031 (940 hom.)
• Consequence: GNAS NM_001410912.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.125
• Publications: 15 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 20-58840400-C-T is Benign according to our data. Variant chr20-58840400-C-T is described in ClinVar as Benign. ClinVar VariationId is 1205855.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001410912.1. 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.294C>T	p.Pro98Pro	synonymous	Exon 1 of 13	NP_057676.1	O95467-1
	GNAS-AS1	NR_185847.1	MANE Select	n.672+1537G>A		intron	N/A
	GNAS	NM_001410912.1		c.-444C>T		5_prime_UTR_premature_start_codon_gain	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.294C>T	p.Pro98Pro	synonymous	Exon 1 of 13	ENSP00000360115.3	O95467-1
	GNAS	ENST00000313949.11	TSL:1	c.294C>T	p.Pro98Pro	synonymous	Exon 1 of 13	ENSP00000323571.7	O95467-1
	GNAS	ENST00000453292.7	TSL:5	c.294C>T	p.Pro98Pro	synonymous	Exon 1 of 12	ENSP00000392000.2	O95467-1

Frequencies

GnomAD3 genomes AF: 0.0479 AC: 7284 AN: 152114 Hom.: 274 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00774

Gnomad SAS AF: 0.0413

Gnomad FIN AF: 0.00706

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0445

GnomAD2 exomes AF: 0.0301 AC: 7510 AN: 249632 AF XY: 0.0300

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.00517

Gnomad FIN exome AF: 0.00898

Gnomad NFE exome AF: 0.0296

Gnomad OTH exome AF: 0.0297

GnomAD4 exome AF: 0.0314 AC: 45843 AN: 1461226 Hom.: 940 Cov.: 36 AF XY: 0.0315 AC XY: 22930 AN XY: 726956

African (AFR) AF: 0.110 AC: 3693 AN: 33472

American (AMR) AF: 0.0167 AC: 746 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 371 AN: 26134

East Asian (EAS) AF: 0.00302 AC: 120 AN: 39698

South Asian (SAS) AF: 0.0409 AC: 3528 AN: 86258

European-Finnish (FIN) AF: 0.0109 AC: 578 AN: 52874

Middle Eastern (MID) AF: 0.0274 AC: 158 AN: 5768

European-Non Finnish (NFE) AF: 0.0311 AC: 34563 AN: 1111910

Other (OTH) AF: 0.0345 AC: 2086 AN: 60388

GnomAD4 genome AF: 0.0481 AC: 7322 AN: 152232 Hom.: 283 Cov.: 32 AF XY: 0.0456 AC XY: 3397 AN XY: 74454

African (AFR) AF: 0.106 AC: 4408 AN: 41506

American (AMR) AF: 0.0264 AC: 405 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3470

East Asian (EAS) AF: 0.00775 AC: 40 AN: 5158

South Asian (SAS) AF: 0.0417 AC: 201 AN: 4820

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

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0297 AC: 2019 AN: 68026

Other (OTH) AF: 0.0545 AC: 115 AN: 2112

Alfa AF: 0.0335 Hom.: 180

Bravo AF: 0.0511

Asia WGS AF: 0.0730 AC: 254 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.94
PhyloP100		0.13
PromoterAI		-0.0017	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: rs1800902; hg19: chr20-57415455; COSMIC: COSV58330333; COSMIC: COSV58330333;