16-90043205-G-C

Variant names:

• chr16-90043205-G-C
• NM_001481.3:c.1297G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001481.3(GAS8):​c.1297G>C​(p.Asp433His) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,459,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GAS8 NM_001481.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.80

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:):

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAS8	NM_001481.3	c.1297G>C	p.Asp433His	missense_variant	Exon 11 of 11	ENST00000268699.9	NP_001472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAS8	ENST00000268699.9	c.1297G>C	p.Asp433His	missense_variant	Exon 11 of 11	1	NM_001481.3	ENSP00000268699.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459750 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1297G>C (p.D433H) alteration is located in exon 11 (coding exon 11) of the GAS8 gene. This alteration results from a G to C substitution at nucleotide position 1297, causing the aspartic acid (D) at amino acid position 433 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;T;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Benign	-0.63	T
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.9	D;D;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.82
MutPred		0.41		.;Loss of ubiquitination at K429 (P = 0.0992);.;
MVP		0.58
MPC		0.14
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-90109613;