chr20-58909030-T-C

Variant names:

• chr20-58909030-T-C
• rs919196
• NM_080425.4:c.2460-132T>C

Variant summary

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

The NM_000516.7(GNAS):​c.531-132T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 796,524 control chromosomes in the GnomAD database, including 15,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3667 hom., cov: 32)
  • Exomes 𝑓: 0.18 (11474 hom.)
• Consequence: GNAS NM_000516.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.03
• 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 Gene-Disease associations (from GenCC):

• McCune-Albright syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• progressive osseous heteroplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• pseudohypoparathyroidism type 1A

  Inheritance: AD, Mitochondrial Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• pseudohypoparathyroidism type 1B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• pseudohypoparathyroidism type 1C

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
• pseudopseudohypoparathyroidism

  Inheritance: AD, Mitochondrial Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 20-58909030-T-C is Benign according to our data. Variant chr20-58909030-T-C is described in ClinVar as Benign. ClinVar VariationId is 1277318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000516.7. 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.2460-132T>C		intron	N/A	NP_536350.2	Q5JWF2-1
	GNAS	NM_000516.7	MANE Select	c.531-132T>C		intron	N/A	NP_000507.1	P63092-1
	GNAS	NM_016592.5	MANE Plus Clinical	c.*437-132T>C		intron	N/A	NP_057676.1	O95467-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.2460-132T>C		intron	N/A	ENSP00000360141.3	Q5JWF2-1
	GNAS	ENST00000371085.8	TSL:1 MANE Select	c.531-132T>C		intron	N/A	ENSP00000360126.3	P63092-1
	GNAS	ENST00000371075.7	TSL:1 MANE Plus Clinical	c.*437-132T>C		intron	N/A	ENSP00000360115.3	O95467-1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32259 AN: 152008 Hom.: 3664 Cov.: 32

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.212

GnomAD4 exome AF: 0.181 AC: 116609 AN: 644398 Hom.: 11474 Cov.: 8 AF XY: 0.177 AC XY: 61788 AN XY: 349712

African (AFR) AF: 0.305 AC: 5484 AN: 18006

American (AMR) AF: 0.130 AC: 5661 AN: 43694

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 4793 AN: 21090

East Asian (EAS) AF: 0.265 AC: 9555 AN: 36044

South Asian (SAS) AF: 0.110 AC: 7612 AN: 69426

European-Finnish (FIN) AF: 0.161 AC: 7743 AN: 48084

Middle Eastern (MID) AF: 0.205 AC: 557 AN: 2712

European-Non Finnish (NFE) AF: 0.185 AC: 68619 AN: 371754

Other (OTH) AF: 0.196 AC: 6585 AN: 33588

GnomAD4 genome AF: 0.212 AC: 32290 AN: 152126 Hom.: 3667 Cov.: 32 AF XY: 0.209 AC XY: 15527 AN XY: 74368

African (AFR) AF: 0.299 AC: 12409 AN: 41482

American (AMR) AF: 0.181 AC: 2771 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 770 AN: 3460

East Asian (EAS) AF: 0.212 AC: 1094 AN: 5160

South Asian (SAS) AF: 0.113 AC: 546 AN: 4828

European-Finnish (FIN) AF: 0.148 AC: 1572 AN: 10594

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12551 AN: 67990

Other (OTH) AF: 0.212 AC: 448 AN: 2116

Alfa AF: 0.198 Hom.: 7756

Bravo AF: 0.220

Asia WGS AF: 0.180 AC: 626 AN: 3478

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	-0.90
CADD	Benign	0.96
DANN	Benign	0.39
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs919196; hg19: chr20-57484085; COSMIC: COSV55672785; COSMIC: COSV55672785;