20-58885457-T-C

Position:

• chr20-58885457-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016592.5(GNAS):​c.*43-10155T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 152,250 control chromosomes in the GnomAD database, including 1,656 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 0.13 (1656 hom., cov: 33)
• Consequence: GNAS NM_016592.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.191

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_016592.5	c.*43-10155T>C		intron_variant		ENST00000371075.7
GNAS	NM_080425.4	c.2069-10155T>C		intron_variant		ENST00000371100.9
LOC101927932	NR_126334.1	n.38-2428A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371075.7	c.*43-10155T>C		intron_variant		1	NM_016592.5
GNAS	ENST00000371100.9	c.2069-10155T>C		intron_variant		5	NM_080425.4
	ENST00000441270.6	n.20-2428A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19433 AN: 152132 Hom.: 1657 Cov.: 33

Gnomad AFR AF: 0.0462

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0466

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.126

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

GnomAD4 genome AF: 0.128 AC: 19421 AN: 152250 Hom.: 1656 Cov.: 33 AF XY: 0.127 AC XY: 9456 AN XY: 74434

Gnomad4 AFR AF: 0.0461

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.0462

Gnomad4 FIN AF: 0.242

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.125

Alfa AF: 0.157 Hom.: 291

Bravo AF: 0.116

Asia WGS AF: 0.0270 AC: 93 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.3
DANN	Benign	0.77

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs62203846; hg19: chr20-57460512;