rs117053233

chr16-90037308-G-Achr16-90037308-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.833G>A(p.Arg278His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,614,006 control chromosomes in the GnomAD database, including 126 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. R278C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0077 (8 hom., cov: 33)
  • Exomes 𝑓: 0.011 (118 hom.)
• Consequence: GAS8 NM_001481.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.74

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=0.0066363215).
• BP6: Variant 16-90037308-G-A is Benign according to our data. Variant chr16-90037308-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-90037308-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00765 (1166/152324) while in subpopulation NFE AF= 0.0134 (911/68024). AF 95% confidence interval is 0.0127. There are 8 homozygotes in gnomad4. There are 566 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAS8	NM_001481.3	c.833G>A	p.Arg278His	missense_variant	7/11	ENST00000268699.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAS8	ENST00000268699.9	c.833G>A	p.Arg278His	missense_variant	7/11	1	NM_001481.3	P4

Frequencies

GnomAD3 genomes AF: 0.00765 AC: 1165 AN: 152206 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00207

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00684

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00768 AC: 1926 AN: 250726 Hom.: 19 AF XY: 0.00782 AC XY: 1060 AN XY: 135558

Gnomad AFR exome AF: 0.00222

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00573

Gnomad FIN exome AF: 0.00472

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.00670

GnomAD4 exome AF: 0.0108 AC: 15840 AN: 1461682 Hom.: 118 Cov.: 31 AF XY: 0.0108 AC XY: 7839 AN XY: 727126

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00601

Gnomad4 FIN exome AF: 0.00489

Gnomad4 NFE exome AF: 0.0129

Gnomad4 OTH exome AF: 0.00793

GnomAD4 genome AF: 0.00765 AC: 1166 AN: 152324 Hom.: 8 Cov.: 33 AF XY: 0.00760 AC XY: 566 AN XY: 74480

Gnomad4 AFR AF: 0.00207

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.00490

Gnomad4 NFE AF: 0.0134

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.0102 Hom.: 10

Bravo AF: 0.00697

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0119 AC: 102

ExAC AF: 0.00845 AC: 1026

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0107

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	Genetics and Molecular Pathology, SA Pathology	Aug 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	GAS8: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D;D;D
MetaRNN	Benign	0.0066	T;T;T
MetaSVM	Benign	-0.39	T
MutationTaster	Benign	0.65	D;D
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.9	D;D;.
REVEL	Benign	0.096
Sift	Uncertain	0.0030	D;D;.
Sift4G	Uncertain	0.010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.18
MVP		0.63
MPC		0.036
ClinPred		0.027	T
GERP RS		4.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.22
gMVP		0.17

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: rs117053233; hg19: chr16-90103716; COSMIC: COSV51942684; COSMIC: COSV51942684;