chr16-90040515-C-T

Position:

• chr16-90040515-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_001481.3(GAS8):​c.1221+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,591,860 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: GAS8 NM_001481.3 splice_region, intron
• Scores: Splicing: ADA: 0.00005388
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.921

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:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000174 (251/1439706) while in subpopulation MID AF= 0.00164 (7/4260). AF 95% confidence interval is 0.000771. There are 1 homozygotes in gnomad4_exome. There are 119 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAS8	NM_001481.3	c.1221+6C>T		splice_region_variant, intron_variant		ENST00000268699.9	NP_001472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAS8	ENST00000268699.9	c.1221+6C>T		splice_region_variant, intron_variant		1	NM_001481.3	ENSP00000268699.4

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152034 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000162

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000217 AC: 46 AN: 212388 Hom.: 0 AF XY: 0.000209 AC XY: 24 AN XY: 114748

Gnomad AFR exome AF: 0.0000776

Gnomad AMR exome AF: 0.000421

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.000746

GnomAD4 exome AF: 0.000174 AC: 251 AN: 1439706 Hom.: 1 Cov.: 32 AF XY: 0.000167 AC XY: 119 AN XY: 714440

Gnomad4 AFR exome AF: 0.0000913

Gnomad4 AMR exome AF: 0.000573

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: 0.000168

Gnomad4 OTH exome AF: 0.000538

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74396

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000302 Hom.: 0

Bravo AF: 0.000280

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 33 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2022

This sequence change falls in intron 9 of the GAS8 gene. It does not directly change the encoded amino acid sequence of the GAS8 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs374119905, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with GAS8-related conditions. ClinVar contains an entry for this variant (Variation ID: 542261). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.1
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000054
dbscSNV1_RF	Benign	0.028
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: rs374119905; hg19: chr16-90106923;