chr12-26065046-G-T

Position:

• chr12-26065046-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001394098.1(RASSF8):​c.652G>T​(p.Val218Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 7.74

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37886807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RASSF8	NM_001394098.1	c.652G>T	p.Val218Leu	missense_variant	4/6	ENST00000689635.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RASSF8	ENST00000689635.1	c.652G>T	p.Val218Leu	missense_variant	4/6		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

Apr 29, 2024

The c.652G>T (p.V218L) 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 652, causing the valine (V) at amino acid position 218 to be replaced by a leucine (L). 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	0.28
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.035	.;T;.;T;T;T;T
Eigen	Benign	0.047
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;.;.;.;D;T;.
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.38	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.061	D
MutationAssessor	Benign	1.6	L;L;L;L;L;.;L
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.1	N;N;.;N;N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.19	T;T;.;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;T;T
Polyphen		0.023	B;P;B;P;P;.;P
Vest4		0.56
MutPred		0.26		Gain of catalytic residue at V218 (P = 0.0015);Gain of catalytic residue at V218 (P = 0.0015);Gain of catalytic residue at V218 (P = 0.0015);Gain of catalytic residue at V218 (P = 0.0015);Gain of catalytic residue at V218 (P = 0.0015);Gain of catalytic residue at V218 (P = 0.0015);Gain of catalytic residue at V218 (P = 0.0015);
MVP		0.92
MPC		0.25
ClinPred		0.83	D
GERP RS		5.0
Varity_R		0.15
gMVP		0.39

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: chr12-26217979;