17-76471053-G-A

Position:

• chr17-76471053-G-A

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.*580C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0265 in 153,876 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (89 hom., cov: 33)
  • Exomes 𝑓: 0.023 (0 hom.)
• Consequence: RHBDF2 NM_001005498.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.809

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=-0.89).
• BP6: Variant 17-76471053-G-A is Benign according to our data. Variant chr17-76471053-G-A is described in ClinVar as [Benign]. Clinvar id is 325403.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHBDF2	NM_001005498.4	c.*580C>T		3_prime_UTR_variant	19/19	ENST00000675367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHBDF2	ENST00000675367.1	c.*580C>T		3_prime_UTR_variant	19/19		NM_001005498.4	P1
RHBDF2	ENST00000313080.8	c.*580C>T		3_prime_UTR_variant	19/19	1
RHBDF2	ENST00000590168.5	n.2503C>T		non_coding_transcript_exon_variant	12/12	1
RHBDF2	ENST00000591885.5			downstream_gene_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 4040 AN: 152148 Hom.: 87 Cov.: 33

Gnomad AFR AF: 0.00734

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0545

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.0686

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0292

GnomAD4 exome AF: 0.0230 AC: 37 AN: 1610 Hom.: 0 Cov.: 0 AF XY: 0.0225 AC XY: 19 AN XY: 846

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0420

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: 0.0221

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0265 AC: 4042 AN: 152266 Hom.: 89 Cov.: 33 AF XY: 0.0283 AC XY: 2107 AN XY: 74440

Gnomad4 AFR AF: 0.00732

Gnomad4 AMR AF: 0.0549

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.0686

Gnomad4 NFE AF: 0.0283

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0188 Hom.: 13

Bravo AF: 0.0247

Asia WGS AF: 0.0140 AC: 49 AN: 3476

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 12, 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	-0.89
CADD	Benign	1.2
DANN	Benign	0.81

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs111924263; hg19: chr17-74467135;