rs868044

chr16-90036425-G-A

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.595G>A(p.Glu199Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,612,348 control chromosomes in the GnomAD database, including 269 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. E199E) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0060 (33 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (236 hom.)
• Consequence: GAS8 NM_001481.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.01

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=0.002479434).
• BP6: Variant 16-90036425-G-A is Benign according to our data. Variant chr16-90036425-G-A is described in ClinVar as [Benign]. Clinvar id is 475567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAS8	NM_001481.3	c.595G>A	p.Glu199Lys	missense_variant	6/11	ENST00000268699.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAS8	ENST00000268699.9	c.595G>A	p.Glu199Lys	missense_variant	6/11	1	NM_001481.3	P4

Frequencies

GnomAD3 genomes AF: 0.00597 AC: 908 AN: 152200 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.0150 AC: 3759 AN: 250638 Hom.: 205 AF XY: 0.0110 AC XY: 1491 AN XY: 135460

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00218

Gnomad SAS exome AF: 0.00236

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000415

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.00342 AC: 4992 AN: 1460030 Hom.: 236 Cov.: 30 AF XY: 0.00291 AC XY: 2114 AN XY: 726002

Gnomad4 AFR exome AF: 0.000957

Gnomad4 AMR exome AF: 0.0956

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00182

Gnomad4 SAS exome AF: 0.00235

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000221

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.00597 AC: 909 AN: 152318 Hom.: 33 Cov.: 33 AF XY: 0.00670 AC XY: 499 AN XY: 74484

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.0484

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00366

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00118 Hom.: 6

Bravo AF: 0.0117

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.0116 AC: 1408

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Feb 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D;D
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.2	N;N;.
REVEL	Benign	0.24
Sift	Benign	0.15	T;T;.
Sift4G	Benign	0.34	T;T;T
Polyphen		0.28	.;B;.
Vest4		0.34
MPC		0.026
ClinPred		0.028	T
GERP RS		5.6
Varity_R		0.19
gMVP		0.51

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: rs868044; hg19: chr16-90102833;