17-76470935-G-C

Position:

• chr17-76470935-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001005498.4(RHBDF2):​c.*698C>G variant causes a 3 prime UTR 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 NM_001005498.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0340

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 Benign. Variant got -14 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 id is 325400.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHBDF2	NM_001005498.4	c.*698C>G		3_prime_UTR_variant	19/19	ENST00000675367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHBDF2	ENST00000675367.1	c.*698C>G		3_prime_UTR_variant	19/19		NM_001005498.4	P1
RHBDF2	ENST00000313080.8	c.*698C>G		3_prime_UTR_variant	19/19	1
RHBDF2	ENST00000590168.5	n.2621C>G		non_coding_transcript_exon_variant	12/12	1

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

Gnomad4 AMR exome AF: 0.750

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.205

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

Gnomad4 AFR AF: 0.233

Gnomad4 AMR AF: 0.440

Gnomad4 ASJ AF: 0.354

Gnomad4 EAS AF: 0.614

Gnomad4 SAS AF: 0.395

Gnomad4 FIN AF: 0.419

Gnomad4 NFE AF: 0.321

Gnomad4 OTH AF: 0.320

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Palmoplantar keratoderma-esophageal carcinoma syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.76
DANN	Benign	0.66

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs8150; hg19: chr17-74467017;