rs387907129
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate
The NM_001005498.4(RHBDF2):c.470T>C(p.Ile157Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,451,728 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
RHBDF2
NM_001005498.4 missense, splice_region
NM_001005498.4 missense, splice_region
Scores
7
8
4
Splicing: ADA: 0.1621
2
Clinical Significance
Conservation
PhyloP100: 9.29
Genes affected
RHBDF2 (HGNC:20788): (rhomboid 5 homolog 2) Predicted to enable protein transporter activity. Predicted to be involved in negative regulation of protein secretion and regulation of epidermal growth factor receptor signaling pathway. Located in plasma membrane. Implicated in palmoplantar keratoderma-esophageal carcinoma syndrome. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-76479008-A-G is Pathogenic according to our data. Variant chr17-76479008-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 31178.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RHBDF2 | NM_001005498.4 | c.470T>C | p.Ile157Thr | missense_variant, splice_region_variant | 6/19 | ENST00000675367.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RHBDF2 | ENST00000675367.1 | c.470T>C | p.Ile157Thr | missense_variant, splice_region_variant | 6/19 | NM_001005498.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000207 AC: 3AN: 1451728Hom.: 0 Cov.: 36 AF XY: 0.00000277 AC XY: 2AN XY: 720958
GnomAD4 exome
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3
AN:
1451728
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Cov.:
36
AF XY:
AC XY:
2
AN XY:
720958
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Palmoplantar keratoderma-esophageal carcinoma syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 10, 2012 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 11, 2023 | For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 31178). This missense change has been observed in individuals with tylosis with esophageal cancer (PMID: 22265016). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 186 of the RHBDF2 protein (p.Ile186Thr). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;.
REVEL
Uncertain
Sift
Pathogenic
D;.
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Gain of phosphorylation at I186 (P = 0.0101);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at