NM_000516.7:c.1113C>T

Variant names:

• chr20-58910757-C-T
• rs8386
• NM_080425.4:c.3042C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000516.7(GNAS):​c.1113C>T​(p.Asn371Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,613,866 control chromosomes in the GnomAD database, including 1,341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (633 hom., cov: 32)
  • Exomes 𝑓: 0.016 (708 hom.)
• Consequence: GNAS NM_000516.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.08
• Publications: 28 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 20-58910757-C-T is Benign according to our data. Variant chr20-58910757-C-T is described in ClinVar as Benign. ClinVar VariationId is 1166174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.168 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.3042C>T	p.Asn1014Asn	synonymous	Exon 13 of 13	NP_536350.2	Q5JWF2-1
	GNAS	NM_000516.7	MANE Select	c.1113C>T	p.Asn371Asn	synonymous	Exon 13 of 13	NP_000507.1	P63092-1
	GNAS	NM_016592.5	MANE Plus Clinical	c.*1019C>T		3_prime_UTR	Exon 13 of 13	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.3042C>T	p.Asn1014Asn	synonymous	Exon 13 of 13	ENSP00000360141.3	Q5JWF2-1
	GNAS	ENST00000371085.8	TSL:1 MANE Select	c.1113C>T	p.Asn371Asn	synonymous	Exon 13 of 13	ENSP00000360126.3	P63092-1
	GNAS	ENST00000676826.2		c.3045C>T	p.Asn1015Asn	synonymous	Exon 13 of 13	ENSP00000504675.2	A0A7I2V5R6

Frequencies

GnomAD3 genomes AF: 0.0568 AC: 8645 AN: 152148 Hom.: 633 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0253

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.0359

GnomAD2 exomes AF: 0.0218 AC: 5490 AN: 251460 AF XY: 0.0189

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.0199

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00323

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0162 AC: 23698 AN: 1461600 Hom.: 708 Cov.: 32 AF XY: 0.0157 AC XY: 11394 AN XY: 727122

African (AFR) AF: 0.180 AC: 6038 AN: 33470

American (AMR) AF: 0.0154 AC: 689 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0212 AC: 555 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.0109 AC: 936 AN: 86258

European-Finnish (FIN) AF: 0.00300 AC: 160 AN: 53420

Middle Eastern (MID) AF: 0.0366 AC: 211 AN: 5768

European-Non Finnish (NFE) AF: 0.0124 AC: 13821 AN: 1111744

Other (OTH) AF: 0.0213 AC: 1285 AN: 60388

GnomAD4 genome AF: 0.0568 AC: 8655 AN: 152266 Hom.: 633 Cov.: 32 AF XY: 0.0552 AC XY: 4113 AN XY: 74456

African (AFR) AF: 0.171 AC: 7117 AN: 41520

American (AMR) AF: 0.0252 AC: 386 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0110 AC: 53 AN: 4824

European-Finnish (FIN) AF: 0.00386 AC: 41 AN: 10616

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0131 AC: 891 AN: 68032

Other (OTH) AF: 0.0355 AC: 75 AN: 2114

Alfa AF: 0.0259 Hom.: 500

Bravo AF: 0.0628

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.0164

EpiControl AF: 0.0157

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.95
PhyloP100		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	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: rs8386; hg19: chr20-57485812; COSMIC: COSV55686986; COSMIC: COSV55686986;