rs884928

chr16-90031453-G-Achr16-90031453-G-Cchr16-90031453-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001481.3(GAS8):c.245G>A(p.Arg82Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00261 in 1,600,554 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R82W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (10 hom.)
• Consequence: GAS8 NM_001481.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.62

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006713599).
• BP6: Variant 16-90031453-G-A is Benign according to our data. Variant chr16-90031453-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00208 (317/152338) while in subpopulation AMR AF= 0.00301 (46/15306). AF 95% confidence interval is 0.00234. There are 0 homozygotes in gnomad4. There are 155 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAS8	NM_001481.3	c.245G>A	p.Arg82Gln	missense_variant	3/11	ENST00000268699.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAS8	ENST00000268699.9	c.245G>A	p.Arg82Gln	missense_variant	3/11	1	NM_001481.3	P4

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 316 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00240 AC: 525 AN: 219044 Hom.: 3 AF XY: 0.00215 AC XY: 255 AN XY: 118582

Gnomad AFR exome AF: 0.000296

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.000449

Gnomad SAS exome AF: 0.0000356

Gnomad FIN exome AF: 0.000374

Gnomad NFE exome AF: 0.00278

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.00266 AC: 3858 AN: 1448216 Hom.: 10 Cov.: 32 AF XY: 0.00257 AC XY: 1849 AN XY: 719286

Gnomad4 AFR exome AF: 0.000241

Gnomad4 AMR exome AF: 0.00117

Gnomad4 ASJ exome AF: 0.0192

Gnomad4 EAS exome AF: 0.000103

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000324

Gnomad4 NFE exome AF: 0.00282

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.00208 AC: 317 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.00208 AC XY: 155 AN XY: 74504

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00343 Hom.: 3

Bravo AF: 0.00215

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000684 AC: 3

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00179 AC: 216

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 33 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 27, 2019	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 08, 2020

- -

GAS8-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.0067	T;T;T
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.4	D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0070	D;T;D
Polyphen		1.0	.;.;D
Vest4		0.69
MVP		0.52
MPC		0.15
ClinPred		0.055	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.33

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: rs884928; hg19: chr16-90097861; COSMIC: COSV99064915; COSMIC: COSV99064915;