20-58854572-C-T

Variant names:

• chr20-58854572-C-T
• rs61749698
• ENST00000676826.2:c.1307C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_080425.4(GNAS):​c.1307C>T​(p.Ala436Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign 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. A436S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNAS NM_080425.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.04

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06449184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNAS	NM_016592.5	c.*42+13686C>T		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	ENST00000676826.2	c.1307C>T	p.Ala436Val	missense_variant	Exon 1 of 13			ENSP00000504675.2
GNAS	ENST00000371102.8	c.1307C>T	p.Ala436Val	missense_variant	Exon 1 of 12	5		ENSP00000360143.4
GNAS	ENST00000371075.7	c.*42+13686C>T		intron_variant	Intron 1 of 12	1	NM_016592.5	ENSP00000360115.3
GNAS	ENST00000663479.2	c.-39+12697C>T		intron_variant	Intron 1 of 12			ENSP00000499353.2
GNAS	ENST00000462499.6	c.-39+12697C>T		intron_variant	Intron 1 of 11	2		ENSP00000499758.2
GNAS	ENST00000467227.6	c.-39+10498C>T		intron_variant	Intron 2 of 12	3		ENSP00000499681.2
GNAS	ENST00000453292.7	c.*42+13686C>T		intron_variant	Intron 1 of 11	5		ENSP00000392000.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1384836 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 686670

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.86
DANN	Benign	0.91
DEOGEN2	Benign	0.26	T;.;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.42	T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.064	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L;.;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.24	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.36	T;D;T
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.0020	B;.;.
Vest4		0.059
MutPred		0.29		Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);
MVP		0.53
MPC		0.41
ClinPred		0.13	T
GERP RS		-4.3
Varity_R		0.027
gMVP		0.13

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61749698; hg19: chr20-57429627;