rs17178299

Positions:

• chr16-90037251-G-A
• chr16-90037251-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001481.3(GAS8):​c.776G>A​(p.Arg259Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0571 in 1,611,484 control chromosomes in the GnomAD database, including 3,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R259R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.046 (216 hom., cov: 33)
  • Exomes 𝑓: 0.058 (2881 hom.)
• Consequence: GAS8 NM_001481.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.70

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=0.0015008748).
• BP6: Variant 16-90037251-G-A is Benign according to our data. Variant chr16-90037251-G-A is described in ClinVar as [Benign]. Clinvar id is 402892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAS8	NM_001481.3	c.776G>A	p.Arg259Gln	missense_variant	7/11	ENST00000268699.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAS8	ENST00000268699.9	c.776G>A	p.Arg259Gln	missense_variant	7/11	1	NM_001481.3	P4

Frequencies

GnomAD3 genomes AF: 0.0458 AC: 6962 AN: 152128 Hom.: 215 Cov.: 33

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.0505

Gnomad AMR AF: 0.0253

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.0272

Gnomad FIN AF: 0.0757

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0622

Gnomad OTH AF: 0.0358

GnomAD3 exomes AF: 0.0523 AC: 12981 AN: 248434 Hom.: 495 AF XY: 0.0511 AC XY: 6862 AN XY: 134294

Gnomad AFR exome AF: 0.00975

Gnomad AMR exome AF: 0.0370

Gnomad ASJ exome AF: 0.0479

Gnomad EAS exome AF: 0.121

Gnomad SAS exome AF: 0.0185

Gnomad FIN exome AF: 0.0777

Gnomad NFE exome AF: 0.0566

Gnomad OTH exome AF: 0.0470

GnomAD4 exome AF: 0.0582 AC: 84987 AN: 1459238 Hom.: 2881 Cov.: 31 AF XY: 0.0571 AC XY: 41409 AN XY: 725666

Gnomad4 AFR exome AF: 0.00757

Gnomad4 AMR exome AF: 0.0337

Gnomad4 ASJ exome AF: 0.0477

Gnomad4 EAS exome AF: 0.0726

Gnomad4 SAS exome AF: 0.0206

Gnomad4 FIN exome AF: 0.0770

Gnomad4 NFE exome AF: 0.0626

Gnomad4 OTH exome AF: 0.0599

GnomAD4 genome AF: 0.0457 AC: 6960 AN: 152246 Hom.: 216 Cov.: 33 AF XY: 0.0458 AC XY: 3408 AN XY: 74416

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.0252

Gnomad4 ASJ AF: 0.0507

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.0274

Gnomad4 FIN AF: 0.0757

Gnomad4 NFE AF: 0.0622

Gnomad4 OTH AF: 0.0364

Alfa AF: 0.0556 Hom.: 577

Bravo AF: 0.0405

TwinsUK AF: 0.0704 AC: 261

ALSPAC AF: 0.0625 AC: 241

ESP6500AA AF: 0.0114 AC: 50

ESP6500EA AF: 0.0600 AC: 516

ExAC AF: 0.0498 AC: 6042

Asia WGS AF: 0.0760 AC: 262 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Primary ciliary dyskinesia 33 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.90	D;D;D
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.0014	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	N;N;.
REVEL	Benign	0.13
Sift	Uncertain	0.0090	D;D;.
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.77	.;P;.
Vest4		0.055
MPC		0.022
ClinPred		0.024	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.10
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17178299; hg19: chr16-90103659; COSMIC: COSV51946631; COSMIC: COSV51946631;