NM_080425.4:c.628G>A

Variant names:

• chr20-58853893-G-A
• rs61749696
• NM_080425.4:c.628G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_080425.4(GNAS):​c.628G>A​(p.Ala210Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,449,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A210S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GNAS NM_080425.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -1.96
• Publications: 18 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=0.05431351).
• BS2: High AC in GnomAdExome4 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.628G>A	p.Ala210Thr	missense	Exon 1 of 13	NP_536350.2	Q5JWF2-1
	GNAS	NM_016592.5	MANE Plus Clinical	c.*42+13007G>A		intron	N/A	NP_057676.1	O95467-1
	GNAS	NM_001410913.1		c.628G>A	p.Ala210Thr	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.628G>A	p.Ala210Thr	missense	Exon 1 of 13	ENSP00000360141.3	Q5JWF2-1
	GNAS	ENST00000676826.2		c.628G>A	p.Ala210Thr	missense	Exon 1 of 13	ENSP00000504675.2	A0A7I2V5R6
	GNAS	ENST00000371102.8	TSL:5	c.628G>A	p.Ala210Thr	missense	Exon 1 of 12	ENSP00000360143.4	Q5JWF2-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000448 AC: 1 AN: 223074 AF XY: 0.00000822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1449042 Hom.: 0 Cov.: 33 AF XY: 0.00000417 AC XY: 3 AN XY: 719754

African (AFR) AF: 0.00 AC: 0 AN: 33228

American (AMR) AF: 0.00 AC: 0 AN: 42536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25878

East Asian (EAS) AF: 0.0000511 AC: 2 AN: 39138

South Asian (SAS) AF: 0.00 AC: 0 AN: 84532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1106466

Other (OTH) AF: 0.00 AC: 0 AN: 59934

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000829 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	GNAS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.047
DANN	Benign	0.59
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.90	L
PhyloP100		-2.0
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.16
Sift	Benign	0.42	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.079	B
Vest4		0.052
MutPred		0.21		Gain of phosphorylation at A210 (P = 0.0024)
MVP		0.46
MPC		0.39
ClinPred		0.037	T
GERP RS		-2.1
Varity_R		0.042
gMVP		0.080
Mutation Taster		=93/7	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs61749696; hg19: chr20-57428948; COSMIC: COSV58339485; COSMIC: COSV58339485;