20-58853461-G-A

Variant names:

• chr20-58853461-G-A
• rs200924357
• NM_080425.4:c.196G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_080425.4(GNAS):​c.196G>A​(p.Glu66Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000269 in 1,612,222 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: GNAS NM_080425.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:3 O:1
• Conservation: PhyloP100: 1.19
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046685934).
• BP6: Variant 20-58853461-G-A is Benign according to our data. Variant chr20-58853461-G-A is described in ClinVar as Benign. ClinVar VariationId is 134498.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00135 (206/152302) while in subpopulation AFR AF = 0.00467 (194/41570). AF 95% confidence interval is 0.00413. There are 0 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 206 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	NM_080425.4	MANE Plus Clinical	c.196G>A	p.Glu66Lys	missense	Exon 1 of 13	NP_536350.2
	GNAS	NM_016592.5	MANE Plus Clinical	c.*42+12575G>A		intron	N/A	NP_057676.1
	GNAS	NM_001410913.1		c.196G>A	p.Glu66Lys	missense	Exon 1 of 12	NP_001397842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.196G>A	p.Glu66Lys	missense	Exon 1 of 13	ENSP00000360141.3
	GNAS	ENST00000676826.2		c.196G>A	p.Glu66Lys	missense	Exon 1 of 13	ENSP00000504675.2
	GNAS	ENST00000371102.8	TSL:5	c.196G>A	p.Glu66Lys	missense	Exon 1 of 12	ENSP00000360143.4

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000338 AC: 83 AN: 245572 AF XY: 0.000194

Gnomad AFR exome AF: 0.00464

Gnomad AMR exome AF: 0.000350

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000901

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000156 AC: 228 AN: 1459920 Hom.: 1 Cov.: 33 AF XY: 0.000109 AC XY: 79 AN XY: 726228

African (AFR) AF: 0.00572 AC: 191 AN: 33420

American (AMR) AF: 0.000292 AC: 13 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52656

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111408

Other (OTH) AF: 0.000332 AC: 20 AN: 60328

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.00120 AC XY: 89 AN XY: 74474

African (AFR) AF: 0.00467 AC: 194 AN: 41570

American (AMR) AF: 0.000457 AC: 7 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000533 Hom.: 0

Bravo AF: 0.00163

ESP6500AA AF: 0.00290 AC: 11

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000331 AC: 40

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	7.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.0047	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.0	L
PhyloP100		1.2
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.18
Sift	Benign	0.23	T
Sift4G	Uncertain	0.0040	D
Polyphen		0.027	B
Vest4		0.18
MVP		0.23
MPC		0.46
ClinPred		0.0044	T
GERP RS		3.6
PromoterAI		0.013	Neutral
Varity_R		0.046
gMVP		0.43
Mutation Taster		=94/6	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs200924357; hg19: chr20-57428516; COSMIC: COSV58344210; COSMIC: COSV58344210;