Variant chr12-26064870-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001394098.1(RASSF8):c.476G>T(p.Cys159Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

RASSF8
NM_001394098.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.09

Variant links:

Genes affected

RASSF8 (HGNC:13232): (Ras association domain family member 8) This gene encodes a member of the Ras-assocation domain family (RASSF) of tumor suppressor proteins. This gene is essential for maintaining adherens junction function in epithelial cells and has a role in epithelial cell migration. It is a lung tumor suppressor gene candidate. A chromosomal translocation t(12;22)(p11.2;q13.3) leading to the fusion of this gene and the FBLN1 gene is found in a complex type of synpolydactyly. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2011]

RASSF8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20332569).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASSF8	NM_001394098.1 linkuse as main transcript	c.476G>T	p.Cys159Phe	missense_variant	4/6	ENST00000689635.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASSF8	ENST00000689635.1 linkuse as main transcript	c.476G>T	p.Cys159Phe	missense_variant	4/6		NM_001394098.1	P1	Q8NHQ8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727234

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2022

The c.476G>T (p.C159F) alteration is located in exon 3 (coding exon 2) of the RASSF8 gene. This alteration results from a G to T substitution at nucleotide position 476, causing the cysteine (C) at amino acid position 159 to be replaced by a phenylalanine (F). 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

Benign

0.092

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.033

.;T;.;T;T;T;.;T;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.77

T;.;.;.;T;T;T;.;T

M_CAP

Benign

0.0068

MetaRNN

Benign

0.15

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L;L;L;L;.;.;L;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.5

N;N;.;N;N;N;N;N;N

REVEL

Benign

0.082

Sift

Benign

0.19

T;T;.;T;T;T;T;T;D

Sift4G

Benign

0.71

T;T;T;T;T;T;T;T;D

Polyphen

0.90

P;P;P;P;P;.;.;P;.

Vest4

0.15

MutPred

0.32

Loss of stability (P = 0.0332);Loss of stability (P = 0.0332);Loss of stability (P = 0.0332);Loss of stability (P = 0.0332);Loss of stability (P = 0.0332);Loss of stability (P = 0.0332);Loss of stability (P = 0.0332);Loss of stability (P = 0.0332);Loss of stability (P = 0.0332);

MVP

0.043

MPC

0.26

ClinPred

0.67

GERP RS

3.8

Varity_R

0.32

gMVP

0.22

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

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