rs145962792

chr16-90040361-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001481.3(GAS8):c.1073A>G(p.Gln358Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00223 in 1,608,366 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (6 hom.)
• Consequence: GAS8 NM_001481.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.17

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]

URAHP (HGNC:43695): (urate (hydroxyiso-) hydrolase, pseudogene) Predicted to enable hydroxyisourate hydrolase activity. Predicted to be involved in allantoin metabolic process; purine-containing compound catabolic process; and urate catabolic process. Predicted to be active in peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010979295).
• BP6: Variant 16-90040361-A-G is Benign according to our data. Variant chr16-90040361-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 542269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00167 (254/152366) while in subpopulation NFE AF= 0.00253 (172/68034). AF 95% confidence interval is 0.00222. There are 0 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAS8	NM_001481.3	c.1073A>G	p.Gln358Arg	missense_variant	9/11	ENST00000268699.9
URAHP	NR_027335.2	n.749T>C		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAS8	ENST00000268699.9	c.1073A>G	p.Gln358Arg	missense_variant	9/11	1	NM_001481.3	P4
URAHP	ENST00000409873.5	n.749T>C		non_coding_transcript_exon_variant	5/5	1

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 254 AN: 152248 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00140 AC: 334 AN: 238878 Hom.: 1 AF XY: 0.00140 AC XY: 181 AN XY: 129342

Gnomad AFR exome AF: 0.000794

Gnomad AMR exome AF: 0.000297

Gnomad ASJ exome AF: 0.00838

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000992

Gnomad NFE exome AF: 0.00207

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.00229 AC: 3332 AN: 1456000 Hom.: 6 Cov.: 32 AF XY: 0.00223 AC XY: 1614 AN XY: 723672

Gnomad4 AFR exome AF: 0.000360

Gnomad4 AMR exome AF: 0.000204

Gnomad4 ASJ exome AF: 0.00858

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000945

Gnomad4 NFE exome AF: 0.00268

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.00167 AC: 254 AN: 152366 Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74508

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00253

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00246 Hom.: 3

Bravo AF: 0.00173

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00125 AC: 151

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GAS8-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

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

Primary ciliary dyskinesia 33 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.7	D;D;.
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.013	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.50
MVP		0.58
MPC		0.15
ClinPred		0.064	T
GERP RS		5.8
Varity_R		0.85
gMVP		0.41

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: rs145962792; hg19: chr16-90106769; COSMIC: COSV51943556; COSMIC: COSV51943556;