Variant 4-73598649-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_177532.5(RASSF6):c.135A>T(p.Leu45Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000581 in 1,376,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000058 ( 0 hom. )

Consequence

RASSF6
NM_177532.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.909

Variant links:

Genes affected

RASSF6 (HGNC:20796): (Ras association domain family member 6) This gene encodes a member of the Ras-association domain family (RASSF). Members of this family form the core of a highly conserved tumor suppressor network, the Salvador-Warts-Hippo (SWH) pathway. The protein encoded by this gene is a Ras effector protein that induces apoptosis. A genomic region containing this gene has been linked to susceptibility to viral bronchiolitis. Alternative splicing results in multiple transcript variants and protein isoforms. [provided by RefSeq, Jul 2012]

RASSF6 links:

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ACMG classification

Classification made for transcript

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=0.27528802).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASSF6	NM_177532.5 linkuse as main transcript	c.135A>T	p.Leu45Phe	missense_variant	3/11	ENST00000307439.10	NP_803876.1	Q6ZTQ3-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RASSF6	ENST00000307439.10 linkuse as main transcript	c.135A>T	p.Leu45Phe	missense_variant	3/11	1	NM_177532.5	ENSP00000303877.5	Q6ZTQ3-2
RASSF6	ENST00000395777.6 linkuse as main transcript	c.135A>T	p.Leu45Phe	missense_variant	3/10	1		ENSP00000379123.2	Q6ZTQ3-4
RASSF6	ENST00000335049.5 linkuse as main transcript	c.109-5056A>T		intron_variant		1		ENSP00000335582.5	Q6ZTQ3-3
RASSF6	ENST00000342081.7 linkuse as main transcript	c.231A>T	p.Leu77Phe	missense_variant	3/11	2		ENSP00000340578.3	Q6ZTQ3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000581

AC:

AN:

1376654

Hom.:

Cov.:

AF XY:

0.00000582

AC XY:

AN XY:

687236

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000763

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

Sep 29, 2023

The c.231A>T (p.L77F) alteration is located in exon 3 (coding exon 3) of the RASSF6 gene. This alteration results from a A to T substitution at nucleotide position 231, causing the leucine (L) at amino acid position 77 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

0.080

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.012

.;T;.

Eigen

Benign

-0.032

Eigen_PC

Benign

-0.051

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.73

T;T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

.;M;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.035

D;D;D

Sift4G

Benign

0.15

T;T;T

Polyphen

0.94, 0.94

.;P;P

Vest4

0.37

MutPred

0.56

.;Gain of sheet (P = 0.0827);.;

MVP

0.48

MPC

0.0076

ClinPred

0.71

GERP RS

3.3

Varity_R

0.093

gMVP

0.21

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