chr20-58900136-A-T

Position:

• chr20-58900136-A-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001309883.1(GNAS):​c.*464A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. 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 0.0 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000072 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNAS NM_001309883.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42

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]

GNAS (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNAS	NM_000516.7	c.257+1151A>T		intron_variant		ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*160+1151A>T		intron_variant		ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.257+1151A>T		intron_variant		1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000371075.7	c.*160+1151A>T		intron_variant		1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2186+1151A>T		intron_variant				ENSP00000504675.2
GNAS	ENST00000371102.8	c.2142-3392A>T		intron_variant		5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.257+1151A>T		intron_variant		1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.213-3392A>T		intron_variant		1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.80+1151A>T		intron_variant		5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.80+1151A>T		intron_variant		5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.80+1151A>T		intron_variant				ENSP00000499353.2
GNAS	ENST00000462499.6	c.36-3392A>T		intron_variant		2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.36-3392A>T		intron_variant		3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.36-3392A>T		intron_variant		2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.36-3392A>T		intron_variant		5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.36-3392A>T		intron_variant		5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.36-3392A>T		intron_variant		5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.36-3392A>T		intron_variant		3		ENSP00000499443.2
GNAS	ENST00000461152.6	c.*125-3392A>T		intron_variant		5		ENSP00000499274.1
GNAS	ENST00000453292.7	c.*116-3392A>T		intron_variant		5		ENSP00000392000.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151914 Hom.: 0 Cov.: 30 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000716 AC: 3 AN: 419016 Hom.: 0 Cov.: 0 AF XY: 0.0000135 AC XY: 3 AN XY: 221588

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 151914 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74188

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.16
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs13831; hg19: chr20-57475191;