rs773018940

Positions:

• chr16-90031452-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001481.3(GAS8):​c.244C>T​(p.Arg82Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000487 in 1,601,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R82Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: GAS8 NM_001481.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40

Genes affected

GAS8 (HGNC:4166): (growth arrest specific 8) This gene includes 11 exons spanning 25 kb and maps to a region of chromosome 16 that is sometimes deleted in breast and prostrate cancer. The second intron contains an apparently intronless gene, C16orf3, that is transcribed in the opposite orientation. This gene is a putative tumor suppressor gene. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2065013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAS8	NM_001481.3	c.244C>T	p.Arg82Trp	missense_variant	3/11	ENST00000268699.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAS8	ENST00000268699.9	c.244C>T	p.Arg82Trp	missense_variant	3/11	1	NM_001481.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000999 AC: 22 AN: 220224 Hom.: 0 AF XY: 0.0000921 AC XY: 11 AN XY: 119378

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000164

Gnomad ASJ exome AF: 0.000840

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000106

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000611

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000476 AC: 69 AN: 1448944 Hom.: 0 Cov.: 32 AF XY: 0.0000514 AC XY: 37 AN XY: 719762

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.000191

Gnomad4 ASJ exome AF: 0.000580

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000355

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000253

Gnomad4 OTH exome AF: 0.000167

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74446

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000629 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000661 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 33 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2022

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 82 of the GAS8 protein (p.Arg82Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with GAS8-related conditions. ClinVar contains an entry for this variant (Variation ID: 571141). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	32
DANN	Pathogenic	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Uncertain	-0.26	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.9	D;D;D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.83
MutPred		0.22		.;.;Loss of MoRF binding (P = 0.0966);
MVP		0.55
MPC		0.15
ClinPred		0.83	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs773018940; hg19: chr16-90097860;