4-73581819-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000307439.10(RASSF6):​c.719G>A​(p.Gly240Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000028 in 1,606,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

RASSF6
ENST00000307439.10 missense, splice_region

Scores

7
5
7
Splicing: ADA: 0.9234
1
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.79
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.792

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RASSF6NM_177532.5 linkuse as main transcriptc.719G>A p.Gly240Glu missense_variant, splice_region_variant 8/11 ENST00000307439.10 NP_803876.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RASSF6ENST00000307439.10 linkuse as main transcriptc.719G>A p.Gly240Glu missense_variant, splice_region_variant 8/111 NM_177532.5 ENSP00000303877 P1Q6ZTQ3-2
RASSF6ENST00000335049.5 linkuse as main transcriptc.683G>A p.Gly228Glu missense_variant, splice_region_variant 7/101 ENSP00000335582 Q6ZTQ3-3
RASSF6ENST00000395777.6 linkuse as main transcriptc.617G>A p.Gly206Glu missense_variant, splice_region_variant 7/101 ENSP00000379123 Q6ZTQ3-4
RASSF6ENST00000342081.7 linkuse as main transcriptc.815G>A p.Gly272Glu missense_variant, splice_region_variant 8/112 ENSP00000340578 Q6ZTQ3-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152082
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000240
AC:
6
AN:
250438
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135392
show subpopulations
Gnomad AFR exome
AF:
0.0000618
Gnomad AMR exome
AF:
0.0000291
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000353
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000296
AC:
43
AN:
1454878
Hom.:
0
Cov.:
29
AF XY:
0.0000304
AC XY:
22
AN XY:
724096
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000349
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000325
Gnomad4 OTH exome
AF:
0.0000333
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152082
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74288
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000691
Hom.:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1

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 submitterclinical testingAmbry GeneticsMar 04, 2024The c.815G>A (p.G272E) alteration is located in exon 8 (coding exon 8) of the RASSF6 gene. This alteration results from a G to A substitution at nucleotide position 815, causing the glycine (G) at amino acid position 272 to be replaced by a glutamic acid (E). 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
Pathogenic
0.57
BayesDel_addAF
Benign
-0.033
T
BayesDel_noAF
Benign
-0.10
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Benign
0.090
.;T;.;.
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.83
T;T;T;T
M_CAP
Benign
0.082
D
MetaRNN
Pathogenic
0.79
D;D;D;D
MetaSVM
Benign
-0.59
T
MutationAssessor
Uncertain
2.8
.;M;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.50
T
PROVEAN
Pathogenic
-7.7
D;D;D;D
REVEL
Uncertain
0.35
Sift
Uncertain
0.0010
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
.;D;D;D
Vest4
0.72
MVP
0.46
MPC
0.018
ClinPred
0.99
D
GERP RS
5.4
Varity_R
0.88
gMVP
0.60

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.92
dbscSNV1_RF
Pathogenic
0.81
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs148110920; hg19: chr4-74447536; API