rs387907130

Variant names:

• chr17-76478999-G-A
• rs387907130
• NM_001005498.4:c.479C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001005498.4(RHBDF2):​c.479C>T​(p.Pro160Leu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P160P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHBDF2 NM_001005498.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.15
• Publications: 16 publications found

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]

RHBDF2 Gene-Disease associations (from GenCC):

• palmoplantar keratoderma-esophageal carcinoma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804
• PP5: Variant 17-76478999-G-A is Pathogenic according to our data. Variant chr17-76478999-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 31179.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHBDF2	NM_001005498.4	c.479C>T	p.Pro160Leu	missense_variant	Exon 6 of 19	ENST00000675367.1	NP_001005498.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHBDF2	ENST00000675367.1	c.479C>T	p.Pro160Leu	missense_variant	Exon 6 of 19		NM_001005498.4	ENSP00000501790.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Palmoplantar keratoderma-esophageal carcinoma syndrome Pathogenic:2

Sep 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 189 of the RHBDF2 protein (p.Pro189Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with esophageal cancer (PMID: 22265016). ClinVar contains an entry for this variant (Variation ID: 31179). 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. Experimental studies have shown that this missense change affects RHBDF2 function (PMID: 28655741, 30197081). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.3	M;.
PhyloP100		8.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.8	D;.
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.21	T;T
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.37		Gain of helix (P = 0.0022);.;
MVP		0.82
MPC		1.2
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.55
gMVP		0.75
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387907130; hg19: chr17-74475081; COSMIC: COSV100489511; COSMIC: COSV100489511;