Variant 4-73576293-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000307439.10(RASSF6):c.956C>T(p.Ala319Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,557,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A319T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

RASSF6
ENST00000307439.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.15

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.004099965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASSF6	NM_177532.5 linkuse as main transcript	c.956C>T	p.Ala319Val	missense_variant	11/11	ENST00000307439.10	NP_803876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASSF6	ENST00000307439.10 linkuse as main transcript	c.956C>T	p.Ala319Val	missense_variant	11/11	1	NM_177532.5	ENSP00000303877	P1	Q6ZTQ3-2
RASSF6	ENST00000335049.5 linkuse as main transcript	c.920C>T	p.Ala307Val	missense_variant	10/10	1		ENSP00000335582		Q6ZTQ3-3
RASSF6	ENST00000395777.6 linkuse as main transcript	c.854C>T	p.Ala285Val	missense_variant	10/10	1		ENSP00000379123		Q6ZTQ3-4
RASSF6	ENST00000342081.7 linkuse as main transcript	c.1052C>T	p.Ala351Val	missense_variant	11/11	2		ENSP00000340578		Q6ZTQ3-1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00750

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000960

GnomAD3 exomes

AF:

0.000299

AC:

AN:

243804

Hom.:

AF XY:

0.000319

AC XY:

AN XY:

131794

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.0000905

Gnomad ASJ exome

AF:

0.00522

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000126

Gnomad OTH exome

AF:

0.000506

GnomAD4 exome

AF:

0.000168

AC:

236

AN:

1405808

Hom.:

Cov.:

AF XY:

0.000185

AC XY:

130

AN XY:

702114

show subpopulations

Gnomad4 AFR exome

AF:

0.0000626

Gnomad4 AMR exome

AF:

0.000209

Gnomad4 ASJ exome

AF:

0.00575

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000478

Gnomad4 OTH exome

AF:

0.000445

GnomAD4 genome

AF:

0.000243

AC:

AN:

152008

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00750

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000960

Alfa

AF:

0.00130

Hom.:

Bravo

AF:

0.000196

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000274

EpiControl

AF:

0.000178

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

Jan 10, 2023

The c.1052C>T (p.A351V) alteration is located in exon 11 (coding exon 11) of the RASSF6 gene. This alteration results from a C to T substitution at nucleotide position 1052, causing the alanine (A) at amino acid position 351 to be replaced by a valine (V). 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

0.11

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.0086

.;T;.;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.69

T;T;T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.0041

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

.;L;.;.

MutationTaster

Benign

0.80

D;D;D;D

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.024

Sift

Benign

0.55

T;T;T;T

Sift4G

Benign

0.51

T;T;T;T

Polyphen

0.29, 0.14

.;B;B;B

Vest4

0.12

MVP

0.19

MPC

0.0049

ClinPred

0.016

GERP RS

3.4

Varity_R

0.062

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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