rs4812042

Positions:

• chr20-58886860-G-A
• chr20-58886860-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_016592.5(GNAS):​c.*43-8752G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 152,142 control chromosomes in the GnomAD database, including 28,729 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.61 (28729 hom., cov: 33)
• Consequence: GNAS NM_016592.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.207

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_016592.5	c.*43-8752G>A		intron_variant		ENST00000371075.7
GNAS	NM_080425.4	c.2069-8752G>A		intron_variant		ENST00000371100.9
LOC101927932	NR_126334.1	n.37+1914C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371075.7	c.*43-8752G>A		intron_variant		1	NM_016592.5
GNAS	ENST00000371100.9	c.2069-8752G>A		intron_variant		5	NM_080425.4
	ENST00000441270.6	n.19+1914C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.611 AC: 92912 AN: 152024 Hom.: 28702 Cov.: 33

Gnomad AFR AF: 0.533

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.639

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.718

Gnomad SAS AF: 0.711

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.628

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.611 AC: 92984 AN: 152142 Hom.: 28729 Cov.: 33 AF XY: 0.614 AC XY: 45659 AN XY: 74374

Gnomad4 AFR AF: 0.533

Gnomad4 AMR AF: 0.639

Gnomad4 ASJ AF: 0.662

Gnomad4 EAS AF: 0.718

Gnomad4 SAS AF: 0.710

Gnomad4 FIN AF: 0.644

Gnomad4 NFE AF: 0.628

Gnomad4 OTH AF: 0.632

Alfa AF: 0.632 Hom.: 29376

Bravo AF: 0.610

Asia WGS AF: 0.736 AC: 2559 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.67

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4812042; hg19: chr20-57461915;