rs577386316

chr20-58854444-G-GGCAGCCCCT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_016592.5(GNAS):c.*42+13567_*42+13575dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,576,028 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (12 hom.)
• Consequence: GNAS NM_016592.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:4 O:1
• Conservation: PhyloP100: 3.26

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 -10 ACMG points.

• BP6: Variant 20-58854444-G-GGCAGCCCCT is Benign according to our data. Variant chr20-58854444-G-GGCAGCCCCT is described in ClinVar as [Benign]. Clinvar id is 134477.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00705 (1072/152082) while in subpopulation AFR AF= 0.0242 (1004/41494). AF 95% confidence interval is 0.023. There are 9 homozygotes in gnomad4. There are 495 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 SM gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_080425.4	c.1188_1196dup	p.Ala398_Ala400dup	inframe_insertion	1/13	ENST00000371100.9
GNAS	NM_016592.5	c.*42+13567_*42+13575dup		intron_variant		ENST00000371075.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371100.9	c.1188_1196dup	p.Ala398_Ala400dup	inframe_insertion	1/13	5	NM_080425.4
GNAS	ENST00000371075.7	c.*42+13567_*42+13575dup		intron_variant		1	NM_016592.5

Frequencies

GnomAD3 genomes AF: 0.00704 AC: 1070 AN: 151964 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

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: 0.000250

Gnomad OTH AF: 0.00719

GnomAD3 exomes AF: 0.00122 AC: 224 AN: 183804 Hom.: 1 AF XY: 0.000973 AC XY: 98 AN XY: 100746

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000231

Gnomad OTH exome AF: 0.000409

GnomAD4 exome AF: 0.000770 AC: 1097 AN: 1423946 Hom.: 12 Cov.: 34 AF XY: 0.000680 AC XY: 480 AN XY: 705462

Gnomad4 AFR exome AF: 0.0249

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000121

Gnomad4 OTH exome AF: 0.00188

GnomAD4 genome AF: 0.00705 AC: 1072 AN: 152082 Hom.: 9 Cov.: 33 AF XY: 0.00666 AC XY: 495 AN XY: 74370

Gnomad4 AFR AF: 0.0242

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.00384 Hom.: 0

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2 Other:1

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

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	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs577386316; hg19: chr20-57429499;