17-76479963-G-C

Variant names:

• chr17-76479963-G-C
• rs3826287
• NM_001005498.4:c.151-109C>G

Variant summary

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

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.47
• Publications: 8 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, G2P, Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005498.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHBDF2	NM_001005498.4	MANE Select	c.151-109C>G		intron	N/A	NP_001005498.2	Q6PJF5-2
	RHBDF2	NM_024599.5		c.151-22C>G		intron	N/A	NP_078875.4	Q6PJF5-1
	RHBDF2	NM_001376228.1		c.151-109C>G		intron	N/A	NP_001363157.1	Q6PJF5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHBDF2	ENST00000675367.1	MANE Select	c.151-109C>G		intron	N/A	ENSP00000501790.1	Q6PJF5-2
	RHBDF2	ENST00000313080.8	TSL:1	c.151-22C>G		intron	N/A	ENSP00000322775.3	Q6PJF5-1
	RHBDF2	ENST00000878663.1		c.151-22C>G		intron	N/A	ENSP00000548722.1

Frequencies

GnomAD3 genomes AF: 0.445 AC: 63774 AN: 143468 Hom.: 14760 Cov.: 23

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

GnomAD2 exomes AF: 0.489 AC: 66440 AN: 135882 AF XY: 0.487

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 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.: 22 AF XY: 0.469 AC XY: 307882 AN XY: 656774

African (AFR) AF: 0.284 AC: 8334 AN: 29300

American (AMR) AF: 0.610 AC: 15633 AN: 25646

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 10798 AN: 22272

East Asian (EAS) AF: 0.625 AC: 22837 AN: 36522

South Asian (SAS) AF: 0.448 AC: 32657 AN: 72824

European-Finnish (FIN) AF: 0.488 AC: 23787 AN: 48724

Middle Eastern (MID) AF: 0.372 AC: 2008 AN: 5402

European-Non Finnish (NFE) AF: 0.466 AC: 484163 AN: 1038708

Other (OTH) AF: 0.463 AC: 25555 AN: 55208

GnomAD4 genome AF: 0.445 AC: 63817 AN: 143562 Hom.: 14778 Cov.: 23 AF XY: 0.451 AC XY: 31330 AN XY: 69408

African (AFR) AF: 0.305 AC: 11518 AN: 37818

American (AMR) AF: 0.560 AC: 7960 AN: 14212

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1715 AN: 3434

East Asian (EAS) AF: 0.635 AC: 3163 AN: 4980

South Asian (SAS) AF: 0.473 AC: 2152 AN: 4550

European-Finnish (FIN) AF: 0.528 AC: 4623 AN: 8758

Middle Eastern (MID) AF: 0.388 AC: 101 AN: 260

European-Non Finnish (NFE) AF: 0.468 AC: 31195 AN: 66682

Other (OTH) AF: 0.439 AC: 864 AN: 1970

Alfa AF: 0.444 Hom.: 2864

Bravo AF: 0.432

Asia WGS AF: 0.533 AC: 1850 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Palmoplantar keratoderma-esophageal carcinoma syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.53
DANN	Benign	0.40
PhyloP100		-1.5
BranchPoint Hunter		2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3826287; hg19: chr17-74476045;