20-58903708-G-C

Position:

• chr20-58903708-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP3

The NM_000516.7(GNAS):​c.349G>C​(p.Val117Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V117M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.59

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000516.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-58903708-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445504.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNAS. . Gene score misZ 2.6546 (greater than the threshold 3.09). Trascript score misZ 4.8361 (greater than threshold 3.09). GenCC has associacion of gene with ACTH-independent macronodular adrenal hyperplasia 1, pseudohypoparathyroidism type 1B, pseudohypoparathyroidism type 1C, pseudohypoparathyroidism type 1A, progressive osseous heteroplasia, pseudopseudohypoparathyroidism, McCune-Albright syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_080425.4	c.2278G>C	p.Val760Leu	missense_variant	5/13	ENST00000371100.9
GNAS	NM_000516.7	c.349G>C	p.Val117Leu	missense_variant	5/13	ENST00000371085.8
GNAS	NM_016592.5	c.*255G>C		3_prime_UTR_variant	5/13	ENST00000371075.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371100.9	c.2278G>C	p.Val760Leu	missense_variant	5/13	5	NM_080425.4
GNAS	ENST00000371085.8	c.349G>C	p.Val117Leu	missense_variant	5/13	1	NM_000516.7
GNAS	ENST00000371075.7	c.*255G>C		3_prime_UTR_variant	5/13	1	NM_016592.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461752 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727194

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;.;.;.;D;.;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.4	.;.;.;.;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.6	D;D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.018	D;D;T;.;D;T;T;D;.
Sift4G	Benign	0.072	T;T;T;T;T;T;T;T;T
Polyphen		0.76	P;.;.;.;.;B;.;B;.
Vest4		0.51
MutPred		0.56		Gain of glycosylation at P759 (P = 0.1187);.;.;.;.;.;.;.;.;
MVP		1.0
MPC		1.2
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.87

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: chr20-57478763;