Genetic Variant RHBDF2:c.151-109C>G (chr17-76479963-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001005498.4(RHBDF2):c.151-109C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 1,478,168 control chromosomes in the GnomAD database, including 163,007 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.44 ( 14778 hom., cov: 23)

Exomes 𝑓: 0.47 ( 148229 hom. )

Consequence

RHBDF2
NM_001005498.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.47

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 17-76479963-G-C is Benign according to our data. Variant chr17-76479963-G-C is described in ClinVar as [Benign]. Clinvar id is 1243766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHBDF2	NM_001005498.4 link	c.151-109C>G		intron_variant	Intron 3 of 18	ENST00000675367.1	NP_001005498.2	Q6PJF5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHBDF2	ENST00000675367.1 link	c.151-109C>G		intron_variant	Intron 3 of 18		NM_001005498.4	ENSP00000501790.1		Q6PJF5-2

Frequencies

GnomAD3 genomes

AF:

0.445

AC:

63774

AN:

143468

Hom.:

14760

Cov.:

show subpopulations

Gnomad AFR

AF:

0.305

Gnomad AMI

AF:

0.586

Gnomad AMR

AF:

0.559

Gnomad ASJ

AF:

0.499

Gnomad EAS

AF:

0.636

Gnomad SAS

AF:

0.472

Gnomad FIN

AF:

0.528

Gnomad MID

AF:

0.388

Gnomad NFE

AF:

0.468

Gnomad OTH

AF:

0.434

GnomAD3 exomes

AF:

0.489

AC:

66440

AN:

135882

Hom.:

16716

AF XY:

0.487

AC XY:

35279

AN XY:

72430

show subpopulations

Gnomad AFR exome

AF:

0.290

Gnomad AMR exome

AF:

0.622

Gnomad ASJ exome

AF:

0.482

Gnomad EAS exome

AF:

0.631

Gnomad SAS exome

AF:

0.452

Gnomad FIN exome

AF:

0.496

Gnomad NFE exome

AF:

0.467

Gnomad OTH exome

AF:

0.478

GnomAD4 exome

AF:

0.469

AC:

625772

AN:

1334606

Hom.:

148229

Cov.:

AF XY:

0.469

AC XY:

307882

AN XY:

656774

show subpopulations

Gnomad4 AFR exome

AF:

0.284

Gnomad4 AMR exome

AF:

0.610

Gnomad4 ASJ exome

AF:

0.485

Gnomad4 EAS exome

AF:

0.625

Gnomad4 SAS exome

AF:

0.448

Gnomad4 FIN exome

AF:

0.488

Gnomad4 NFE exome

AF:

0.466

Gnomad4 OTH exome

AF:

0.463

GnomAD4 genome

AF:

0.445

AC:

63817

AN:

143562

Hom.:

14778

Cov.:

AF XY:

0.451

AC XY:

31330

AN XY:

69408

show subpopulations

Gnomad4 AFR

AF:

0.305

Gnomad4 AMR

AF:

0.560

Gnomad4 ASJ

AF:

0.499

Gnomad4 EAS

AF:

0.635

Gnomad4 SAS

AF:

0.473

Gnomad4 FIN

AF:

0.528

Gnomad4 NFE

AF:

0.468

Gnomad4 OTH

AF:

0.439

Alfa

AF:

0.444

Hom.:

2864

Bravo

AF:

0.432

Asia WGS

AF:

0.533

AC:

1850

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Palmoplantar keratoderma-esophageal carcinoma syndrome

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.53

DANN

Benign

0.40

BranchPoint Hunter

2.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over