chr20-58854572-C-A

Variant names:

• chr20-58854572-C-A
• rs61749698
• NM_080425.4:c.1307C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_080425.4(GNAS):​c.1307C>A​(p.Ala436Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 1,534,760 control chromosomes in the GnomAD database, including 1,835 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.073 (820 hom., cov: 32)
  • Exomes 𝑓: 0.027 (1015 hom.)
• Consequence: GNAS NM_080425.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -3.04
• Publications: 30 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001532495).
• BP6: Variant 20-58854572-C-A is Benign according to our data. Variant chr20-58854572-C-A is described in ClinVar as Benign. ClinVar VariationId is 134479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080425.4. 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.1307C>A	p.Ala436Asp	missense	Exon 1 of 13	NP_536350.2	Q5JWF2-1
	GNAS	NM_016592.5	MANE Plus Clinical	c.*42+13686C>A		intron	N/A	NP_057676.1	O95467-1
	GNAS	NM_001410913.1		c.1307C>A	p.Ala436Asp	missense	Exon 1 of 12	NP_001397842.1	Q5JWE9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAS	ENST00000371100.9	TSL:5 MANE Plus Clinical	c.1307C>A	p.Ala436Asp	missense	Exon 1 of 13	ENSP00000360141.3	Q5JWF2-1
	GNAS	ENST00000676826.2		c.1307C>A	p.Ala436Asp	missense	Exon 1 of 13	ENSP00000504675.2	A0A7I2V5R6
	GNAS	ENST00000371102.8	TSL:5	c.1307C>A	p.Ala436Asp	missense	Exon 1 of 12	ENSP00000360143.4	Q5JWF2-2

Frequencies

GnomAD3 genomes AF: 0.0724 AC: 10852 AN: 149844 Hom.: 812 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0540

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0195

Gnomad SAS AF: 0.0249

Gnomad FIN AF: 0.00579

Gnomad MID AF: 0.0455

Gnomad NFE AF: 0.0267

Gnomad OTH AF: 0.0601

GnomAD4 exome AF: 0.0265 AC: 36724 AN: 1384812 Hom.: 1015 Cov.: 34 AF XY: 0.0264 AC XY: 18132 AN XY: 686660

African (AFR) AF: 0.191 AC: 5569 AN: 29212

American (AMR) AF: 0.0495 AC: 1894 AN: 38282

Ashkenazi Jewish (ASJ) AF: 0.00654 AC: 167 AN: 25528

East Asian (EAS) AF: 0.0189 AC: 688 AN: 36404

South Asian (SAS) AF: 0.0276 AC: 2231 AN: 80718

European-Finnish (FIN) AF: 0.0114 AC: 404 AN: 35504

Middle Eastern (MID) AF: 0.0212 AC: 119 AN: 5626

European-Non Finnish (NFE) AF: 0.0219 AC: 23580 AN: 1075598

Other (OTH) AF: 0.0358 AC: 2072 AN: 57940

GnomAD4 genome AF: 0.0727 AC: 10898 AN: 149948 Hom.: 820 Cov.: 32 AF XY: 0.0697 AC XY: 5114 AN XY: 73338

African (AFR) AF: 0.195 AC: 7819 AN: 40176

American (AMR) AF: 0.0540 AC: 820 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3468

East Asian (EAS) AF: 0.0196 AC: 99 AN: 5060

South Asian (SAS) AF: 0.0251 AC: 120 AN: 4774

European-Finnish (FIN) AF: 0.00579 AC: 61 AN: 10536

Middle Eastern (MID) AF: 0.0524 AC: 15 AN: 286

European-Non Finnish (NFE) AF: 0.0267 AC: 1803 AN: 67496

Other (OTH) AF: 0.0673 AC: 139 AN: 2066

Alfa AF: 0.0487 Hom.: 49

TwinsUK AF: 0.0318 AC: 118

ALSPAC AF: 0.0252 AC: 97

ExAC AF: 0.00957 AC: 996

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Pseudopseudohypoparathyroidism;C0242292:McCune-Albright syndrome;C0334041:Progressive osseous heteroplasia;C1857451:ACTH-independent macronodular adrenal hyperplasia 1;C1864100:Pseudohypoparathyroidism type 1B;C2932716:Pseudohypoparathyroidism type 1C;C3494506:Pseudohypoparathyroidism type I A;C4540135:Pituitary adenoma 3, multiple types (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.70
DANN	Benign	0.58
DEOGEN2	Benign	0.25	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.65	N
PhyloP100		-3.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.22
Sift	Benign	0.27	T
Sift4G	Uncertain	0.033	D
Polyphen		0.0020	B
Vest4		0.12
MVP		0.18
MPC		0.62
ClinPred		0.14	T
GERP RS		-4.3
Varity_R		0.10
gMVP		0.19
Mutation Taster		=98/2	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs61749698; hg19: chr20-57429627; COSMIC: COSV58328304; COSMIC: COSV58328304;