rs1057518907

Variant names:

• chr20-58891811-C-A
• NM_000516.7:c.85C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-58891811-C-A
• chr20-58891811-C-G
• chr20-58891811-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000516.7(GNAS):​c.85C>A​(p.Gln29Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000875 in 1,142,418 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.20

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a signal_peptide (size 45) in uniprot entity GNAS3_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000516.7
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the GNAS gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 58 curated pathogenic missense variants (we use a threshold of 10). The gene has 64 curated benign missense variants. Gene score misZ: 2.6546 (below the threshold of 3.09). Trascript score misZ: 4.8361 (above the threshold of 3.09). GenCC associations: The gene is linked to ACTH-independent macronodular adrenal hyperplasia 1, pseudohypoparathyroidism type 1B, pseudohypoparathyroidism type 1C, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia, pseudopseudohypoparathyroidism, McCune-Albright syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.85C>A	p.Gln29Lys	missense_variant	Exon 1 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*43-3801C>A		intron_variant	Intron 1 of 12	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.85C>A	p.Gln29Lys	missense_variant	Exon 1 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000354359.12	c.85C>A	p.Gln29Lys	missense_variant	Exon 1 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.85C>A	p.Gln29Lys	missense_variant	Exon 1 of 12	1		ENSP00000360136.3
GNAS	ENST00000371075.7	c.*43-3801C>A		intron_variant	Intron 1 of 12	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000676826.2	c.2069-3801C>A		intron_variant	Intron 1 of 12			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2069-3801C>A		intron_variant	Intron 1 of 11	5		ENSP00000360143.4
GNAS	ENST00000470512.6	c.-39+2458C>A		intron_variant	Intron 1 of 12	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.-39+2262C>A		intron_variant	Intron 2 of 13	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.-38-3801C>A		intron_variant	Intron 1 of 12			ENSP00000499353.2
GNAS	ENST00000462499.6	c.-38-3801C>A		intron_variant	Intron 1 of 11	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.-38-3801C>A		intron_variant	Intron 2 of 12	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.-39+2458C>A		intron_variant	Intron 1 of 11	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.-39+2903C>A		intron_variant	Intron 1 of 11	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.-39+2262C>A		intron_variant	Intron 1 of 11	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.-39+2993C>A		intron_variant	Intron 1 of 11	5		ENSP00000499332.2
GNAS	ENST00000461152.6	c.*51+1022C>A		intron_variant	Intron 1 of 2	5		ENSP00000499274.1
GNAS	ENST00000453292.7	c.*43-3801C>A		intron_variant	Intron 1 of 11	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 8.75e-7 AC: 1 AN: 1142418 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 566350

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000876

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	26
DANN	Benign	0.96
DEOGEN2	Uncertain	0.76	.;D;.;.;D;T;D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.5	M;M;M;M;.;.;.
PROVEAN	Uncertain	-2.5	N;N;N;N;D;N;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0060	D;D;D;D;D;D;D
Sift4G	Benign	0.097	T;T;T;T;T;D;T
Polyphen		0.64, 0.91	.;P;.;P;.;.;.
Vest4		0.36
MutPred		0.54		Gain of methylation at Q29 (P = 0.0357);Gain of methylation at Q29 (P = 0.0357);Gain of methylation at Q29 (P = 0.0357);Gain of methylation at Q29 (P = 0.0357);Gain of methylation at Q29 (P = 0.0357);Gain of methylation at Q29 (P = 0.0357);.;
MVP		0.72
ClinPred		0.70	D
GERP RS		2.1

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-57466866;