rs139167960

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001481.3(GAS8):c.841G>C(p.Asp281His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000427 in 1,614,028 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00060 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00041 ( 1 hom. )

Consequence

GAS8
NM_001481.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 7.20

Variant links:

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]

GAS8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014992714).

BP6

Variant 16-90037316-G-C is Benign according to our data. Variant chr16-90037316-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542273.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000597 (91/152332) while in subpopulation AMR AF= 0.00288 (44/15302). AF 95% confidence interval is 0.0022. There are 1 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAS8	NM_001481.3 linkuse as main transcript	c.841G>C	p.Asp281His	missense_variant	7/11	ENST00000268699.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAS8	ENST00000268699.9 linkuse as main transcript	c.841G>C	p.Asp281His	missense_variant	7/11	1	NM_001481.3	P4	O95995-1

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

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:

0.000514

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000570

AC:

143

AN:

250794

Hom.:

AF XY:

0.000538

AC XY:

AN XY:

135600

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00252

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:

0.000414

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000409

AC:

598

AN:

1461696

Hom.:

Cov.:

AF XY:

0.000414

AC XY:

301

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00295

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000385

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.000597

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000386

Hom.:

Bravo

AF:

0.000929

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000404

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 33

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 06, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 05, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

GAS8-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2023

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.41

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.030

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-0.95

MutationTaster

Benign

0.98

D;D

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.4

N;N;.

REVEL

Benign

0.14

Sift

Uncertain

0.0050

D;D;.

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.90

.;P;.

Vest4

0.33

MVP

0.64

MPC

0.082

ClinPred

0.092

GERP RS

5.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.17

gMVP

0.25

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over