NM_000516.7:c.530+398T>C

Variant names:

• chr20-58905878-T-C
• rs919197
• NM_080425.4:c.2459+398T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000516.7(GNAS):​c.530+398T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 152,046 control chromosomes in the GnomAD database, including 30,265 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.60 (30265 hom., cov: 32)
• Consequence: GNAS NM_000516.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.26
• Publications: 21 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.876 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.2459+398T>C		intron	N/A	NP_536350.2	Q5JWF2-1
	GNAS	NM_000516.7	MANE Select	c.530+398T>C		intron	N/A	NP_000507.1	P63092-1
	GNAS	NM_016592.5	MANE Plus Clinical	c.*436+398T>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.2459+398T>C		intron	N/A	ENSP00000360141.3	Q5JWF2-1
	GNAS	ENST00000371085.8	TSL:1 MANE Select	c.530+398T>C		intron	N/A	ENSP00000360126.3	P63092-1
	GNAS	ENST00000371075.7	TSL:1 MANE Plus Clinical	c.*436+398T>C		intron	N/A	ENSP00000360115.3	O95467-1

Frequencies

GnomAD3 genomes AF: 0.604 AC: 91818 AN: 151928 Hom.: 30212 Cov.: 32

Gnomad AFR AF: 0.883

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.535

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.587

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.605 AC: 91922 AN: 152046 Hom.: 30265 Cov.: 32 AF XY: 0.594 AC XY: 44104 AN XY: 74302

African (AFR) AF: 0.884 AC: 36679 AN: 41512

American (AMR) AF: 0.535 AC: 8163 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2026 AN: 3470

East Asian (EAS) AF: 0.352 AC: 1814 AN: 5156

South Asian (SAS) AF: 0.402 AC: 1937 AN: 4820

European-Finnish (FIN) AF: 0.409 AC: 4303 AN: 10530

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.519 AC: 35281 AN: 67966

Other (OTH) AF: 0.584 AC: 1234 AN: 2114

Alfa AF: 0.541 Hom.: 96454

Bravo AF: 0.623

Asia WGS AF: 0.412 AC: 1431 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.081
DANN	Benign	0.29
PhyloP100		-3.3
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: rs919197; hg19: chr20-57480933;