rs79527543

Variant names:

• chr20-58840821-C-A
• rs79527543
• NM_016592.5:c.715C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-58840821-C-A
• chr20-58840821-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016592.5(GNAS):​c.715C>A​(p.Pro239Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,612,766 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (37 hom.)
• Consequence: GNAS NM_016592.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 1.62
• Publications: 9 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 (MetaRNN=0.0035827458).
• BP6: Variant 20-58840821-C-A is Benign according to our data. Variant chr20-58840821-C-A is described in ClinVar as Benign. ClinVar VariationId is 134490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0119 (1805/152292) while in subpopulation AFR AF = 0.0404 (1680/41564). AF 95% confidence interval is 0.0388. There are 34 homozygotes in GnomAd4. There are 866 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1805 AD,Mitochondrial,Unknown gene.

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.715C>A	p.Pro239Thr	missense	Exon 1 of 13	NP_057676.1
	GNAS-AS1	NR_185847.1	MANE Select	n.672+1116G>T		intron	N/A
	GNAS	NM_001410912.1		c.-23C>A		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.715C>A	p.Pro239Thr	missense	Exon 1 of 13	ENSP00000360115.3
	GNAS	ENST00000313949.11	TSL:1	c.715C>A	p.Pro239Thr	missense	Exon 1 of 13	ENSP00000323571.7
	GNAS	ENST00000453292.7	TSL:5	c.715C>A	p.Pro239Thr	missense	Exon 1 of 12	ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1803 AN: 152174 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0405

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00301 AC: 742 AN: 246336 AF XY: 0.00239

Gnomad AFR exome AF: 0.0437

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000154

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00140 AC: 2041 AN: 1460474 Hom.: 37 Cov.: 35 AF XY: 0.00124 AC XY: 902 AN XY: 726540

African (AFR) AF: 0.0446 AC: 1494 AN: 33478

American (AMR) AF: 0.00181 AC: 81 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52134

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000269 AC: 299 AN: 1111912

Other (OTH) AF: 0.00265 AC: 160 AN: 60382

GnomAD4 genome AF: 0.0119 AC: 1805 AN: 152292 Hom.: 34 Cov.: 32 AF XY: 0.0116 AC XY: 866 AN XY: 74482

African (AFR) AF: 0.0404 AC: 1680 AN: 41564

American (AMR) AF: 0.00594 AC: 91 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68020

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.00469 Hom.: 15

Bravo AF: 0.0138

ESP6500AA AF: 0.0373 AC: 164

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00365 AC: 443

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.6
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.048
Sift	Uncertain	0.010	D
Sift4G	Benign	0.43	T
Polyphen		0.64	P
Vest4		0.49
MVP		0.043
ClinPred		0.0080	T
GERP RS		1.8
PromoterAI		0.062	Neutral
Mutation Taster		=97/3	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs79527543; hg19: chr20-57415876;