rs1555891562

Variant names:

• chr20-58909707-G-A
• rs1555891562
• NM_000516.7:c.742G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000516.7(GNAS):​c.742G>A​(p.Val248Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V248E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAS NM_000516.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.47
• Publications: 0 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 Gene-Disease associations (from GenCC):

• McCune-Albright syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• progressive osseous heteroplasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, NO_KNOWN Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pseudohypoparathyroidism type 1B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• pseudohypoparathyroidism type 1C

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• pseudopseudohypoparathyroidism

  Inheritance: AD, Mitochondrial Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• pseudohypoparathyroidism type 1A

  Inheritance: Mitochondrial, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 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, 6 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 chr20-58909708-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2115614.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant 20-58909707-G-A is Pathogenic according to our data. Variant chr20-58909707-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521825.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_000516.7	c.742G>A	p.Val248Met	missense_variant	Exon 10 of 13	ENST00000371085.8	NP_000507.1
GNAS	NM_016592.5	c.*648G>A		3_prime_UTR_variant	Exon 10 of 13	ENST00000371075.7	NP_057676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNAS	ENST00000371085.8	c.742G>A	p.Val248Met	missense_variant	Exon 10 of 13	1	NM_000516.7	ENSP00000360126.3
GNAS	ENST00000676826.2	c.2674G>A	p.Val892Met	missense_variant	Exon 10 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.2629G>A	p.Val877Met	missense_variant	Exon 9 of 12	5		ENSP00000360143.4
GNAS	ENST00000354359.12	c.745G>A	p.Val249Met	missense_variant	Exon 10 of 13	1		ENSP00000346328.7
GNAS	ENST00000371095.7	c.700G>A	p.Val234Met	missense_variant	Exon 9 of 12	1		ENSP00000360136.3
GNAS	ENST00000470512.6	c.568G>A	p.Val190Met	missense_variant	Exon 10 of 13	5		ENSP00000499552.2
GNAS	ENST00000480232.6	c.568G>A	p.Val190Met	missense_variant	Exon 11 of 14	5		ENSP00000499545.2
GNAS	ENST00000663479.2	c.568G>A	p.Val190Met	missense_variant	Exon 10 of 13			ENSP00000499353.2
GNAS	ENST00000462499.6	c.523G>A	p.Val175Met	missense_variant	Exon 9 of 12	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.523G>A	p.Val175Met	missense_variant	Exon 10 of 13	3		ENSP00000499681.2
GNAS	ENST00000478585.6	c.523G>A	p.Val175Met	missense_variant	Exon 9 of 12	2		ENSP00000499762.2
GNAS	ENST00000481039.6	c.523G>A	p.Val175Met	missense_variant	Exon 9 of 12	5		ENSP00000499767.2
GNAS	ENST00000485673.6	c.523G>A	p.Val175Met	missense_variant	Exon 9 of 12	5		ENSP00000499334.2
GNAS	ENST00000488546.6	c.523G>A	p.Val175Met	missense_variant	Exon 9 of 12	5		ENSP00000499332.2
GNAS	ENST00000492907.6	c.523G>A	p.Val175Met	missense_variant	Exon 9 of 12	3		ENSP00000499443.2
GNAS	ENST00000371075.7	c.*648G>A		3_prime_UTR_variant	Exon 10 of 13	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000453292.7	c.*603G>A		3_prime_UTR_variant	Exon 9 of 12	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

May 24, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D;.;.;D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	.;.;.;H;.;.
PhyloP100		9.5
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.2	N;N;N;N;N;N
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;.;D
Vest4		0.71
MutPred		0.77		Loss of catalytic residue at V891 (P = 0.0116);.;.;.;.;.;
MVP		1.0
MPC		3.1
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.96
Mutation Taster		=19/81	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1555891562; hg19: chr20-57484762; COSMIC: COSV55679305;