rs387907129

Variant names:

• chr17-76479008-A-G
• rs387907129
• NM_001005498.4:c.470T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_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. 3/3 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
• Scores: Splicing: ADA: 0.1621
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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]

ACMG classification

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 rank	MANE	Protein	UniProt
RHBDF2	NM_001005498.4	c.470T>C	p.Ile157Thr	missense_variant, splice_region_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.470T>C	p.Ile157Thr	missense_variant, splice_region_variant	Exon 6 of 19		NM_001005498.4	ENSP00000501790.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1451728 Hom.: 0 Cov.: 36 AF XY: 0.00000277 AC XY: 2 AN XY: 720958

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Palmoplantar keratoderma-esophageal carcinoma syndrome Pathogenic:1

Feb 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Aug 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 31178). 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. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.9	N;.
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.18		Gain of phosphorylation at I186 (P = 0.0101);.;
MVP		0.81
MPC		1.3
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.42
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.16
dbscSNV1_RF	Benign	0.39
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

Publications

LitVar

Other links and lift over

dbSNP: rs387907129; hg19: chr17-74475090;