rs552813440

Variant names:

• chr20-58854727-G-A
• rs552813440
• NM_080425.4:c.1462G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_080425.4(GNAS):​c.1462G>A​(p.Ala488Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000084 in 1,535,354 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A488G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: GNAS NM_080425.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:3 O:1
• Conservation: PhyloP100: 0.139
• Publications: 2 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07264835).
• BP6: Variant 20-58854727-G-A is Benign according to our data. Variant chr20-58854727-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 134496.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 10 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.1462G>A	p.Ala488Thr	missense	Exon 1 of 13	NP_536350.2	Q5JWF2-1
	GNAS	NM_016592.5	MANE Plus Clinical	c.*42+13841G>A		intron	N/A	NP_057676.1	O95467-1
	GNAS	NM_001410913.1		c.1462G>A	p.Ala488Thr	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.1462G>A	p.Ala488Thr	missense	Exon 1 of 13	ENSP00000360141.3	Q5JWF2-1
	GNAS	ENST00000676826.2		c.1462G>A	p.Ala488Thr	missense	Exon 1 of 13	ENSP00000504675.2	A0A7I2V5R6
	GNAS	ENST00000371102.8	TSL:5	c.1462G>A	p.Ala488Thr	missense	Exon 1 of 12	ENSP00000360143.4	Q5JWF2-2

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 151902 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000122 AC: 16 AN: 131196 AF XY: 0.0000833

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000122

Gnomad OTH exome AF: 0.000249

GnomAD4 exome AF: 0.0000860 AC: 119 AN: 1383342 Hom.: 0 Cov.: 34 AF XY: 0.0000864 AC XY: 59 AN XY: 682646

African (AFR) AF: 0.0000317 AC: 1 AN: 31544

American (AMR) AF: 0.000222 AC: 8 AN: 35978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25044

East Asian (EAS) AF: 0.00 AC: 0 AN: 35764

South Asian (SAS) AF: 0.000164 AC: 13 AN: 79112

European-Finnish (FIN) AF: 0.0000292 AC: 1 AN: 34218

Middle Eastern (MID) AF: 0.000583 AC: 3 AN: 5148

European-Non Finnish (NFE) AF: 0.0000806 AC: 87 AN: 1078752

Other (OTH) AF: 0.000104 AC: 6 AN: 57782

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152012 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74286

African (AFR) AF: 0.00 AC: 0 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4808

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67928

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000190 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.0000824 AC: 8

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	GNAS-related disorder (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	0.088
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	7.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.14
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.14	B
Vest4		0.051
MutPred		0.17		Gain of glycosylation at A488 (P = 0.0017)
MVP		0.61
MPC		0.39
ClinPred		0.035	T
GERP RS		-1.3
Varity_R		0.11
gMVP		0.087
Mutation Taster		=96/4	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs552813440; hg19: chr20-57429782; COSMIC: COSV58331928; COSMIC: COSV58331928;