12-26064870-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.09

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]

ACMG classification

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	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	c.476G>T	p.Cys159Phe	missense_variant	4/6		NM_001394098.1	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727234

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	19
Dann	Benign	0.95
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.77	T;.;.;.;T;T;T;.;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L;L;L;.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.50	T
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	D
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

Other links and lift over

dbSNP: rs1943832470; hg19: chr12-26217803;