NM_080425.4:c.988A>G

Variant names:

• chr20-58854253-A-G
• rs201597085
• NM_080425.4:c.988A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_080425.4(GNAS):​c.988A>G​(p.Ile330Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,613,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I330I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: GNAS NM_080425.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• Conservation: PhyloP100: 0.146
• Publications: 8 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06338331).
• BP6: Variant 20-58854253-A-G is Benign according to our data. Variant chr20-58854253-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134492.
• BS2: High AC in GnomAd4 at 6 AD,Mitochondrial,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080425.4. 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.988A>G	p.Ile330Val	missense	Exon 1 of 13	NP_536350.2	Q5JWF2-1
	GNAS	NM_016592.5	MANE Plus Clinical	c.*42+13367A>G		intron	N/A	NP_057676.1	O95467-1
	GNAS	NM_001410913.1		c.988A>G	p.Ile330Val	missense	Exon 1 of 12	NP_001397842.1	Q5JWE9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.988A>G	p.Ile330Val	missense	Exon 1 of 13	ENSP00000360141.3	Q5JWF2-1
	GNAS	ENST00000676826.2		c.988A>G	p.Ile330Val	missense	Exon 1 of 13	ENSP00000504675.2	A0A7I2V5R6
	GNAS	ENST00000371102.8	TSL:5	c.988A>G	p.Ile330Val	missense	Exon 1 of 12	ENSP00000360143.4	Q5JWF2-2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000770 AC: 19 AN: 246786 AF XY: 0.0000892

Gnomad AFR exome AF: 0.0000662

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000334

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.0000359

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1460926 Hom.: 0 Cov.: 33 AF XY: 0.0000454 AC XY: 33 AN XY: 726712

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39694

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86200

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111768

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74448

African (AFR) AF: 0.0000241 AC: 1 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000662 AC: 8

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	GNAS-related disorder (1)
-	1	-	not provided (1)
-	-	1	Pseudopseudohypoparathyroidism;C0242292:McCune-Albright syndrome;C0334041:Progressive osseous heteroplasia;C1857451:ACTH-independent macronodular adrenal hyperplasia 1;C1864100:Pseudohypoparathyroidism type 1B;C2932716:Pseudohypoparathyroidism type 1C;C3494506:Pseudohypoparathyroidism type I A;C4540135:Pituitary adenoma 3, multiple types (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.15
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.27	T
Polyphen		0.010	B
Vest4		0.15
MVP		0.55
MPC		0.34
ClinPred		0.076	T
GERP RS		2.6
Varity_R		0.096
gMVP		0.096
Mutation Taster		=89/11	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs201597085; hg19: chr20-57429308; COSMIC: COSV58339417; COSMIC: COSV58339417;