rs61749695

Positions:

• chr20-58853765-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016592.5(GNAS):​c.*42+12879A>G variant causes a intron 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. 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_016592.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.185

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]

ACMG classification

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/exons	MANE	Protein	UniProt
GNAS	NM_080425.4	c.500A>G	p.Asp167Gly	missense_variant	1/13	ENST00000371100.9	NP_536350.2
GNAS	NM_016592.5	c.*42+12879A>G		intron_variant		ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371100.9	c.500A>G	p.Asp167Gly	missense_variant	1/13	5	NM_080425.4	ENSP00000360141
GNAS	ENST00000371075.7	c.*42+12879A>G		intron_variant		1	NM_016592.5	ENSP00000360115

Frequencies

GnomAD3 genomes AF: 0.00668 AC: 1016 AN: 152138 Hom.: 10 Cov.: 33

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.: 3 AF XY: 0.00127 AC XY: 171 AN XY: 134668

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.: 8 Cov.: 33 AF XY: 0.000601 AC XY: 437 AN XY: 726812

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.: 10 Cov.: 33 AF XY: 0.00635 AC XY: 473 AN XY: 74458

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.: 5

Bravo AF: 0.00756

ESP6500AA AF: 0.0175 AC: 68

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00183 AC: 221

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000594

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2020	- -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.72	T;T;T
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;L
MutationTaster	Benign	1.0	D;D;D;N;N;N;N
PrimateAI	Benign	0.33	T
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	T
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

Other links and lift over

dbSNP: rs61749695; hg19: chr20-57428820; COSMIC: COSV99047795; COSMIC: COSV99047795;