rs532475771

Variant names:

• chr20-58854687-C-A
• rs532475771
• NM_080425.4:c.1422C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-58854687-C-A
• chr20-58854687-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001077490.3(GNAS):​c.1235C>A​(p.Pro412Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/16 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. P412L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNAS NM_001077490.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09543678).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077490.3. 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_080425.4	MANE Plus Clinical	c.1422C>A	p.Pro474Pro	synonymous	Exon 1 of 13	NP_536350.2
	GNAS	NM_016592.5	MANE Plus Clinical	c.*42+13801C>A		intron	N/A	NP_057676.1
	GNAS	NM_001077490.3		c.1235C>A	p.Pro412Gln	missense	Exon 1 of 13	NP_001070958.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.1422C>A	p.Pro474Pro	synonymous	Exon 1 of 13	ENSP00000360141.3
	GNAS	ENST00000676826.2		c.1422C>A	p.Pro474Pro	synonymous	Exon 1 of 13	ENSP00000504675.2
	GNAS	ENST00000371102.8	TSL:5	c.1422C>A	p.Pro474Pro	synonymous	Exon 1 of 12	ENSP00000360143.4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151288 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000587 AC: 71 AN: 120876 AF XY: 0.000480

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.000306

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000208

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000537

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000473 AC: 65 AN: 1373710 Hom.: 0 Cov.: 34 AF XY: 0.0000413 AC XY: 28 AN XY: 677630

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00148 AC: 44 AN: 29824

American (AMR) AF: 0.000145 AC: 5 AN: 34366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24738

East Asian (EAS) AF: 0.0000568 AC: 2 AN: 35200

South Asian (SAS) AF: 0.0000255 AC: 2 AN: 78308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33880

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4822

European-Non Finnish (NFE) AF: 0.00000930 AC: 10 AN: 1075238

Other (OTH) AF: 0.0000349 AC: 2 AN: 57334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000132 AC: 2 AN: 151288 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 73932

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000245 AC: 1 AN: 40786

American (AMR) AF: 0.00 AC: 0 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67908

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000304 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.52
DANN	Benign	0.91
Eigen	Benign	-0.87
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.022	N
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.1	T
PhyloP100		-1.6
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.016
Sift	Benign	0.42	T
Sift4G	Benign	0.20	T
Vest4		0.25
MutPred		0.35		Loss of catalytic residue at P411 (P = 0.004)
MVP		0.13
ClinPred		0.011	T
GERP RS		-2.5
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs532475771; hg19: chr20-57429742;