rs61749695

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_080425.4(GNAS):c.500A>G(p.Asp167Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,613,354 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0067 ( 10 hom., cov: 33)

Exomes 𝑓: 0.00070 ( 8 hom. )

Consequence

GNAS
NM_080425.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 0.185

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003507316).

BP6

Variant 20-58853765-A-G is Benign according to our data. Variant chr20-58853765-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 134478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58853765-A-G is described in Lovd as [Likely_benign]. Variant chr20-58853765-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00669 (1018/152256) while in subpopulation AFR AF= 0.0232 (966/41558). AF 95% confidence interval is 0.022. There are 10 homozygotes in gnomad4. There are 473 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 SM,Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_016592.5 link	c.*42+12879A>G		intron_variant	Intron 1 of 12	ENST00000371075.7	NP_057676.1	O95467-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GNAS	ENST00000676826.2 link	c.500A>G	p.Asp167Gly	missense_variant	Exon 1 of 13			ENSP00000504675.2	A0A7I2V5R6
GNAS	ENST00000371102.8 link	c.500A>G	p.Asp167Gly	missense_variant	Exon 1 of 12	5		ENSP00000360143.4	Q5JWF2-2
GNAS	ENST00000371075.7 link	c.*42+12879A>G		intron_variant	Intron 1 of 12	1	NM_016592.5	ENSP00000360115.3	O95467-1
GNAS	ENST00000663479.2 link	c.-39+11890A>G		intron_variant	Intron 1 of 12			ENSP00000499353.2	A0A590UJQ9
GNAS	ENST00000462499.6 link	c.-39+11890A>G		intron_variant	Intron 1 of 11	2		ENSP00000499758.2	A0A590UK28
GNAS	ENST00000467227.6 link	c.-39+9691A>G		intron_variant	Intron 2 of 12	3		ENSP00000499681.2	A0A590UK28
GNAS	ENST00000453292.7 link	c.*42+12879A>G		intron_variant	Intron 1 of 11	5		ENSP00000392000.2	O95467-1A2A2S1

Frequencies

GnomAD3 genomes

AF:

0.00668

AC:

1016

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0233

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

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:

0.000147

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00168

AC:

416

AN:

247672

Hom.:

AF XY:

0.00127

AC XY:

171

AN XY:

134668

show subpopulations

Gnomad AFR exome

AF:

0.0245

Gnomad AMR exome

AF:

0.000930

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000656

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.000832

GnomAD4 exome

AF:

0.000699

AC:

1022

AN:

1461098

Hom.:

Cov.:

AF XY:

0.000601

AC XY:

437

AN XY:

726812

show subpopulations

Gnomad4 AFR exome

AF:

0.0259

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.00133

GnomAD4 genome

AF:

0.00669

AC:

1018

AN:

152256

Hom.:

Cov.:

AF XY:

0.00635

AC XY:

473

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0232

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00142

Hom.:

Bravo

AF:

0.00756

ESP6500AA

AF:

0.0175

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00183

AC:

221

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000594

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 20, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:1Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;.;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.72

T;T;T

MetaRNN

Benign

0.0035

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.;L

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.0

N;N;N

REVEL

Benign

0.24

Sift

Uncertain

0.0080

D;T;D

Sift4G

Uncertain

0.0080

D;T;D

Polyphen

0.27

B;.;.

Vest4

0.14

MVP

0.44

MPC

0.54

ClinPred

0.019

GERP RS

4.8

Varity_R

0.15

gMVP

0.12

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over