ENST00000590168.5:n.2621C>G

Variant names:

• chr17-76470935-G-C
• rs8150
• ENST00000590168.5:n.2621C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000590168.5(RHBDF2):​n.2621C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 152,196 control chromosomes in the GnomAD database, including 8,860 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8854 hom., cov: 33)
  • Exomes 𝑓: 0.24 (6 hom.)
• Consequence: RHBDF2 ENST00000590168.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0340
• Publications: 26 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-76470935-G-C is Benign according to our data. Variant chr17-76470935-G-C is described in ClinVar as Benign. ClinVar VariationId is 325400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000590168.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHBDF2	NM_001005498.4	MANE Select	c.*698C>G		3_prime_UTR	Exon 19 of 19	NP_001005498.2
	RHBDF2	NR_164785.1		n.3901C>G		non_coding_transcript_exon	Exon 19 of 19
	RHBDF2	NR_164786.1		n.3643C>G		non_coding_transcript_exon	Exon 20 of 20

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHBDF2	ENST00000590168.5	TSL:1	n.2621C>G		non_coding_transcript_exon	Exon 12 of 12
	RHBDF2	ENST00000675367.1	MANE Select	c.*698C>G		3_prime_UTR	Exon 19 of 19	ENSP00000501790.1
	RHBDF2	ENST00000313080.8	TSL:1	c.*698C>G		3_prime_UTR	Exon 19 of 19	ENSP00000322775.3

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49962 AN: 151956 Hom.: 8846 Cov.: 33

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.354

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.419

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.317

GnomAD4 exome AF: 0.242 AC: 30 AN: 124 Hom.: 6 Cov.: 0 AF XY: 0.293 AC XY: 17 AN XY: 58

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.750 AC: 3 AN: 4

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AF: 0.500 AC: 3 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.205 AC: 23 AN: 112

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.329 AC: 49992 AN: 152072 Hom.: 8854 Cov.: 33 AF XY: 0.339 AC XY: 25177 AN XY: 74318

African (AFR) AF: 0.233 AC: 9666 AN: 41480

American (AMR) AF: 0.440 AC: 6719 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 1228 AN: 3466

East Asian (EAS) AF: 0.614 AC: 3178 AN: 5172

South Asian (SAS) AF: 0.395 AC: 1905 AN: 4828

European-Finnish (FIN) AF: 0.419 AC: 4426 AN: 10552

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.321 AC: 21799 AN: 67986

Other (OTH) AF: 0.320 AC: 677 AN: 2116

Alfa AF: 0.222 Hom.: 552

Bravo AF: 0.326

Asia WGS AF: 0.503 AC: 1744 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Palmoplantar keratoderma-esophageal carcinoma syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.76
DANN	Benign	0.66
PhyloP100		0.034
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs8150; hg19: chr17-74467017;