rs1800905

Variant names:

• chr20-58840940-A-G
• rs1800905
• NM_016592.5:c.*42+54A>G

Your query was ambiguous. Multiple possible variants found:

• chr20-58840940-A-G
• chr20-58840940-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016592.5(GNAS):​c.*42+54A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 1,583,672 control chromosomes in the GnomAD database, including 324,911 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26538 hom., cov: 31)
  • Exomes 𝑓: 0.64 (298373 hom.)
• Consequence: GNAS NM_016592.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.631
• Publications: 17 publications found

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-AS1 (HGNC:24872): (GNAS antisense RNA 1) This gene produces a paternally-imprinted antisense RNA transcript that helps regulate the GNAS complex locus, which encodes the alpha subunit of the stimulatory G protein. Defects in this gene are a cause of pseudohypoparathyroidism type Ib.[provided by RefSeq, Jun 2010]

GNAS-AS1 Gene-Disease associations (from GenCC):

• pseudohypoparathyroidism type 1B

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000293655 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 20-58840940-A-G is Benign according to our data. Variant chr20-58840940-A-G is described in ClinVar as Benign. ClinVar VariationId is 1273639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016592.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	NM_016592.5	MANE Plus Clinical	c.*42+54A>G		intron	N/A	NP_057676.1	O95467-1
	GNAS-AS1	NR_185847.1	MANE Select	n.672+997T>C		intron	N/A
	GNAS	NM_001410912.1		c.43+54A>G		intron	N/A	NP_001397841.1	A0A0A0MR13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371075.7	TSL:1 MANE Plus Clinical	c.*42+54A>G		intron	N/A	ENSP00000360115.3	O95467-1
	GNAS	ENST00000313949.11	TSL:1	c.*42+54A>G		intron	N/A	ENSP00000323571.7	O95467-1
	GNAS	ENST00000453292.7	TSL:5	c.*42+54A>G		intron	N/A	ENSP00000392000.2	O95467-1

Frequencies

GnomAD3 genomes AF: 0.579 AC: 87904 AN: 151750 Hom.: 26514 Cov.: 31

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.725

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.680

Gnomad FIN AF: 0.691

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.634

Gnomad OTH AF: 0.554

GnomAD4 exome AF: 0.643 AC: 920601 AN: 1431804 Hom.: 298373 AF XY: 0.644 AC XY: 458657 AN XY: 712202

African (AFR) AF: 0.409 AC: 13429 AN: 32830

American (AMR) AF: 0.670 AC: 28302 AN: 42242

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 13006 AN: 25668

East Asian (EAS) AF: 0.776 AC: 30268 AN: 39010

South Asian (SAS) AF: 0.684 AC: 57524 AN: 84084

European-Finnish (FIN) AF: 0.690 AC: 35009 AN: 50732

Middle Eastern (MID) AF: 0.513 AC: 2932 AN: 5720

European-Non Finnish (NFE) AF: 0.644 AC: 703121 AN: 1092162

Other (OTH) AF: 0.624 AC: 37010 AN: 59356

GnomAD4 genome AF: 0.579 AC: 87978 AN: 151868 Hom.: 26538 Cov.: 31 AF XY: 0.584 AC XY: 43366 AN XY: 74224

African (AFR) AF: 0.421 AC: 17420 AN: 41418

American (AMR) AF: 0.595 AC: 9080 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.512 AC: 1776 AN: 3472

East Asian (EAS) AF: 0.802 AC: 4097 AN: 5106

South Asian (SAS) AF: 0.681 AC: 3276 AN: 4814

European-Finnish (FIN) AF: 0.691 AC: 7295 AN: 10558

Middle Eastern (MID) AF: 0.449 AC: 131 AN: 292

European-Non Finnish (NFE) AF: 0.634 AC: 43062 AN: 67930

Other (OTH) AF: 0.560 AC: 1180 AN: 2108

Alfa AF: 0.596 Hom.: 3598

Bravo AF: 0.567

Asia WGS AF: 0.708 AC: 2458 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.2
DANN	Benign	0.35
PhyloP100		0.63
PromoterAI		0.072	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1800905; hg19: chr20-57415995;