12-26067680-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394098.1(RASSF8):c.1105G>A(p.Glu369Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RASSF8 NM_001394098.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.30

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=0.14958984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASSF8	NM_001394098.1	c.1105G>A	p.Glu369Lys	missense_variant	5/6	ENST00000689635.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASSF8	ENST00000689635.1	c.1105G>A	p.Glu369Lys	missense_variant	5/6		NM_001394098.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jan 11, 2023

The c.1105G>A (p.E369K) alteration is located in exon 4 (coding exon 3) of the RASSF8 gene. This alteration results from a G to A substitution at nucleotide position 1105, causing the glutamic acid (E) at amino acid position 369 to be replaced by a lysine (K). 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	0.12
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;.;.;.;D;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.81	N;N;.;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.032	D;D;.;D;D;D
Sift4G	Uncertain	0.018	D;T;D;T;T;T
Polyphen		0.93	P;P;P;P;P;P
Vest4		0.36
MutPred		0.31		Gain of ubiquitination at E369 (P = 0.0114);Gain of ubiquitination at E369 (P = 0.0114);Gain of ubiquitination at E369 (P = 0.0114);Gain of ubiquitination at E369 (P = 0.0114);Gain of ubiquitination at E369 (P = 0.0114);Gain of ubiquitination at E369 (P = 0.0114);
MVP		0.19
MPC		0.21
ClinPred		0.89	D
GERP RS		5.2
Varity_R		0.13
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-26220613; COSMIC: COSV99280895; COSMIC: COSV99280895;