rs141125763

Positions:

• chr16-90037283-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001481.3(GAS8):​c.808G>C​(p.Ala270Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 1,613,844 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A270V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (12 hom.)
• Consequence: GAS8 NM_001481.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.747

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011502475).
• BP6: Variant 16-90037283-G-C is Benign according to our data. Variant chr16-90037283-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475568.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00148 (226/152328) while in subpopulation SAS AF= 0.0029 (14/4824). AF 95% confidence interval is 0.00188. There are 0 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAS8	NM_001481.3	c.808G>C	p.Ala270Pro	missense_variant	7/11	ENST00000268699.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAS8	ENST00000268699.9	c.808G>C	p.Ala270Pro	missense_variant	7/11	1	NM_001481.3	P4

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 226 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00180 AC: 450 AN: 250464 Hom.: 4 AF XY: 0.00197 AC XY: 267 AN XY: 135408

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.000928

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00364

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00193 AC: 2815 AN: 1461516 Hom.: 12 Cov.: 31 AF XY: 0.00196 AC XY: 1426 AN XY: 727018

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00364

Gnomad4 FIN exome AF: 0.00296

Gnomad4 NFE exome AF: 0.00197

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.00138 AC XY: 103 AN XY: 74476

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.00216

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00172 Hom.: 0

Bravo AF: 0.00116

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00197 AC: 239

EpiCase AF: 0.00262

EpiControl AF: 0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	GAS8: BP4, BS2 -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.808G>C (p.A270P) alteration is located in exon 7 (coding exon 7) of the GAS8 gene. This alteration results from a G to C substitution at nucleotide position 808, causing the alanine (A) at amino acid position 270 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Primary ciliary dyskinesia 33 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.7	D;D;.
REVEL	Benign	0.15
Sift	Benign	0.20	T;T;.
Sift4G	Benign	0.21	T;T;T
Polyphen		0.54	.;P;.
Vest4		0.53
MVP		0.54
MPC		0.034
ClinPred		0.037	T
GERP RS		-0.73
Varity_R		0.30
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141125763; hg19: chr16-90103691; COSMIC: COSV99243830; COSMIC: COSV99243830;