20-58854392-C-T

Variant names:

• chr20-58854392-C-T
• rs61749697
• NM_080425.4:c.1127C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_080425.4(GNAS):​c.1127C>T​(p.Pro376Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0243 in 1,566,182 control chromosomes in the GnomAD database, including 578 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.023 (50 hom., cov: 33)
  • Exomes 𝑓: 0.024 (528 hom.)
• Consequence: GNAS NM_080425.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:4 O:1
• Conservation: PhyloP100: 0.879
• Publications: 16 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=0.0022606552).
• BP6: Variant 20-58854392-C-T is Benign according to our data. Variant chr20-58854392-C-T is described in ClinVar as Benign. ClinVar VariationId is 134483.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0653 is higher than 0.05.

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.1127C>T	p.Pro376Leu	missense	Exon 1 of 13	NP_536350.2
	GNAS	NM_016592.5	MANE Plus Clinical	c.*42+13506C>T		intron	N/A	NP_057676.1
	GNAS	NM_001410913.1		c.1127C>T	p.Pro376Leu	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.1127C>T	p.Pro376Leu	missense	Exon 1 of 13	ENSP00000360141.3
	GNAS	ENST00000676826.2		c.1127C>T	p.Pro376Leu	missense	Exon 1 of 13	ENSP00000504675.2
	GNAS	ENST00000371102.8	TSL:5	c.1127C>T	p.Pro376Leu	missense	Exon 1 of 12	ENSP00000360143.4

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3435 AN: 152180 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0403

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00744

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.0764

Gnomad NFE AF: 0.0279

Gnomad OTH AF: 0.0368

GnomAD2 exomes AF: 0.0224 AC: 3827 AN: 171176 AF XY: 0.0218

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.0276

Gnomad ASJ exome AF: 0.0519

Gnomad EAS exome AF: 0.0000851

Gnomad FIN exome AF: 0.0143

Gnomad NFE exome AF: 0.0285

Gnomad OTH exome AF: 0.0400

GnomAD4 exome AF: 0.0245 AC: 34573 AN: 1413886 Hom.: 528 Cov.: 34 AF XY: 0.0241 AC XY: 16840 AN XY: 699190

African (AFR) AF: 0.0102 AC: 325 AN: 31968

American (AMR) AF: 0.0287 AC: 1078 AN: 37584

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 1249 AN: 25348

East Asian (EAS) AF: 0.0000550 AC: 2 AN: 36384

South Asian (SAS) AF: 0.00606 AC: 490 AN: 80814

European-Finnish (FIN) AF: 0.0140 AC: 684 AN: 48864

Middle Eastern (MID) AF: 0.0710 AC: 405 AN: 5702

European-Non Finnish (NFE) AF: 0.0264 AC: 28732 AN: 1088572

Other (OTH) AF: 0.0274 AC: 1608 AN: 58650

GnomAD4 genome AF: 0.0225 AC: 3433 AN: 152296 Hom.: 50 Cov.: 33 AF XY: 0.0221 AC XY: 1648 AN XY: 74460

African (AFR) AF: 0.0112 AC: 464 AN: 41578

American (AMR) AF: 0.0403 AC: 616 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 172 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.00724 AC: 35 AN: 4832

European-Finnish (FIN) AF: 0.0132 AC: 140 AN: 10626

Middle Eastern (MID) AF: 0.0856 AC: 25 AN: 292

European-Non Finnish (NFE) AF: 0.0279 AC: 1898 AN: 67996

Other (OTH) AF: 0.0364 AC: 77 AN: 2116

Alfa AF: 0.0270 Hom.: 95

Bravo AF: 0.0246

TwinsUK AF: 0.0321 AC: 119

ALSPAC AF: 0.0249 AC: 96

ESP6500AA AF: 0.0117 AC: 45

ESP6500EA AF: 0.0249 AC: 203

ExAC AF: 0.0150 AC: 1754

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2 Other:1

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

not provided Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.88
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.19
Sift	Benign	0.43	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.027	B
Vest4		0.12
MPC		0.42
ClinPred		0.0061	T
GERP RS		3.6
Varity_R		0.062
gMVP		0.20
Mutation Taster		=98/2	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs61749697; hg19: chr20-57429447; COSMIC: COSV58330503; COSMIC: COSV58330503;