rs61749698

chr20-58854572-C-Achr20-58854572-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016592.5(GNAS):c.*42+13686C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 1,534,760 control chromosomes in the GnomAD database, including 1,835 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (820 hom., cov: 32)
  • Exomes 𝑓: 0.027 (1015 hom.)
• Consequence: GNAS NM_016592.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -3.04

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=0.001532495).
• BP6: Variant 20-58854572-C-A is Benign according to our data. Variant chr20-58854572-C-A is described in ClinVar as [Benign]. Clinvar id is 134479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-58854572-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_080425.4	c.1307C>A	p.Ala436Asp	missense_variant	1/13	ENST00000371100.9
GNAS	NM_016592.5	c.*42+13686C>A		intron_variant		ENST00000371075.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371100.9	c.1307C>A	p.Ala436Asp	missense_variant	1/13	5	NM_080425.4
GNAS	ENST00000371075.7	c.*42+13686C>A		intron_variant		1	NM_016592.5

Frequencies

GnomAD3 genomes AF: 0.0724 AC: 10852 AN: 149844 Hom.: 812 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0540

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0195

Gnomad SAS AF: 0.0249

Gnomad FIN AF: 0.00579

Gnomad MID AF: 0.0455

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0601

GnomAD4 exome AF: 0.0265 AC: 36724 AN: 1384812 Hom.: 1015 Cov.: 34 AF XY: 0.0264 AC XY: 18132 AN XY: 686660

Gnomad4 AFR exome AF: 0.191

Gnomad4 AMR exome AF: 0.0495

Gnomad4 ASJ exome AF: 0.00654

Gnomad4 EAS exome AF: 0.0189

Gnomad4 SAS exome AF: 0.0276

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.0219

Gnomad4 OTH exome AF: 0.0358

GnomAD4 genome AF: 0.0727 AC: 10898 AN: 149948 Hom.: 820 Cov.: 32 AF XY: 0.0697 AC XY: 5114 AN XY: 73338

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.0540

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.0196

Gnomad4 SAS AF: 0.0251

Gnomad4 FIN AF: 0.00579

Gnomad4 NFE AF: 0.0267

Gnomad4 OTH AF: 0.0673

Alfa AF: 0.0487 Hom.: 49

TwinsUK AF: 0.0318 AC: 118

ALSPAC AF: 0.0252 AC: 97

ExAC AF: 0.00957 AC: 996

ClinVar

Significance: 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	GeneDx	Nov 05, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Pseudopseudohypoparathyroidism;C0242292:McCune-Albright syndrome;C0334041:Progressive osseous heteroplasia;C1857451:ACTH-independent macronodular adrenal hyperplasia 1;C1864100:Pseudohypoparathyroidism type 1B;C2932716:Pseudohypoparathyroidism type 1C;C3494506:Pseudohypoparathyroidism type I A;C4540135:Pituitary adenoma 3, multiple types Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 21, 2021

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	0.70
Dann	Benign	0.58
DEOGEN2	Benign	0.25	T;.;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.26	T;T;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.65	N;.;N
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.18	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.27	T;T;T
Sift4G	Uncertain	0.033	D;T;D
Polyphen		0.0020	B;.;.
Vest4		0.12
MVP		0.18
MPC		0.62
ClinPred		0.14	T
GERP RS		-4.3
Varity_R		0.10
gMVP		0.19

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61749698; hg19: chr20-57429627; COSMIC: COSV58328304; COSMIC: COSV58328304;