20-58902035-T-C

Position:

• chr20-58902035-T-C

Variant summary

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

The NM_000516.7(GNAS):​c.258-1496T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 151,650 control chromosomes in the GnomAD database, including 26,731 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 0.59 (26731 hom., cov: 29)
• Consequence: GNAS NM_000516.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.298

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_000516.7	c.258-1496T>C		intron_variant		ENST00000371085.8
GNAS	NM_016592.5	c.*161-1493T>C		intron_variant		ENST00000371075.7
GNAS	NM_080425.4	c.2187-1496T>C		intron_variant		ENST00000371100.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371075.7	c.*161-1493T>C		intron_variant		1	NM_016592.5
GNAS	ENST00000371085.8	c.258-1496T>C		intron_variant		1	NM_000516.7
GNAS	ENST00000371100.9	c.2187-1496T>C		intron_variant		5	NM_080425.4

Frequencies

GnomAD3 genomes AF: 0.587 AC: 88878 AN: 151534 Hom.: 26729 Cov.: 29

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.665

Gnomad AMR AF: 0.640

Gnomad ASJ AF: 0.658

Gnomad EAS AF: 0.688

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.615

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

GnomAD4 genome AF: 0.586 AC: 88911 AN: 151650 Hom.: 26731 Cov.: 29 AF XY: 0.593 AC XY: 43927 AN XY: 74106

Gnomad4 AFR AF: 0.449

Gnomad4 AMR AF: 0.640

Gnomad4 ASJ AF: 0.658

Gnomad4 EAS AF: 0.688

Gnomad4 SAS AF: 0.702

Gnomad4 FIN AF: 0.660

Gnomad4 NFE AF: 0.625

Gnomad4 OTH AF: 0.612

Alfa AF: 0.627 Hom.: 49954

Bravo AF: 0.583

Asia WGS AF: 0.676 AC: 2348 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.4
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs6128461; hg19: chr20-57477090;