rs61734730

chr16-90040394-G-A

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.1106G>A(p.Arg369His) variant causes a missense change. The variant allele was found at a frequency of 0.000631 in 1,611,558 control chromosomes in the GnomAD database, including 8 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. R369C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (4 hom.)
• Consequence: GAS8 NM_001481.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.59

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011025161).
• BP6: Variant 16-90040394-G-A is Benign according to our data. Variant chr16-90040394-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00344 (524/152332) while in subpopulation AFR AF= 0.0123 (510/41574). AF 95% confidence interval is 0.0114. There are 4 homozygotes in gnomad4. There are 266 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAS8	NM_001481.3	c.1106G>A	p.Arg369His	missense_variant	9/11	ENST00000268699.9
URAHP	NR_027335.2	n.716C>T		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAS8	ENST00000268699.9	c.1106G>A	p.Arg369His	missense_variant	9/11	1	NM_001481.3	P4
URAHP	ENST00000409873.5	n.716C>T		non_coding_transcript_exon_variant	5/5	1

Frequencies

GnomAD3 genomes AF: 0.00345 AC: 525 AN: 152214 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000918 AC: 225 AN: 245026 Hom.: 1 AF XY: 0.000693 AC XY: 92 AN XY: 132778

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.000410

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000335

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000905

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000338 AC: 493 AN: 1459226 Hom.: 4 Cov.: 32 AF XY: 0.000298 AC XY: 216 AN XY: 725640

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.000514

GnomAD4 genome AF: 0.00344 AC: 524 AN: 152332 Hom.: 4 Cov.: 32 AF XY: 0.00357 AC XY: 266 AN XY: 74490

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000615 Hom.: 1

Bravo AF: 0.00390

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00109 AC: 132

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely 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 23, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.3	D;D;.
REVEL	Benign	0.19
Sift	Uncertain	0.0080	D;D;.
Sift4G	Uncertain	0.019	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.36
MVP		0.66
MPC		0.15
ClinPred		0.037	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.18

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: rs61734730; hg19: chr16-90106802; COSMIC: COSV51942461; COSMIC: COSV51942461;