17-76471082-C-T

Variant names:

• chr17-76471082-C-T
• rs2289801
• NM_001005498.4:c.*551G>A

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.*551G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 156,832 control chromosomes in the GnomAD database, including 177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (174 hom., cov: 33)
  • Exomes 𝑓: 0.024 (3 hom.)
• Consequence: RHBDF2 NM_001005498.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.505
• Publications: 1 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: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-76471082-C-T is Benign according to our data. Variant chr17-76471082-C-T is described in ClinVar as Benign. ClinVar VariationId is 325406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.115 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.*551G>A		3_prime_UTR	Exon 19 of 19	NP_001005498.2	Q6PJF5-2
	RHBDF2	NM_024599.5		c.*551G>A		3_prime_UTR	Exon 19 of 19	NP_078875.4	Q6PJF5-1
	RHBDF2	NM_001376228.1		c.*551G>A		3_prime_UTR	Exon 19 of 19	NP_001363157.1	Q6PJF5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHBDF2	ENST00000675367.1	MANE Select	c.*551G>A		3_prime_UTR	Exon 19 of 19	ENSP00000501790.1	Q6PJF5-2
	RHBDF2	ENST00000313080.8	TSL:1	c.*551G>A		3_prime_UTR	Exon 19 of 19	ENSP00000322775.3	Q6PJF5-1
	RHBDF2	ENST00000590168.5	TSL:1	n.2474G>A		non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes AF: 0.0373 AC: 5666 AN: 152096 Hom.: 172 Cov.: 33

Gnomad AFR AF: 0.0613

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0605

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.0605

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0416

GnomAD4 exome AF: 0.0238 AC: 110 AN: 4618 Hom.: 3 Cov.: 0 AF XY: 0.0298 AC XY: 72 AN XY: 2414

African (AFR) AF: 0.00 AC: 0 AN: 40

American (AMR) AF: 0.0440 AC: 52 AN: 1182

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 1 AN: 28

East Asian (EAS) AF: 0.0286 AC: 2 AN: 70

South Asian (SAS) AF: 0.0773 AC: 28 AN: 362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 56

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.00998 AC: 27 AN: 2706

Other (OTH) AF: 0.00 AC: 0 AN: 170

GnomAD4 genome AF: 0.0373 AC: 5680 AN: 152214 Hom.: 174 Cov.: 33 AF XY: 0.0387 AC XY: 2883 AN XY: 74426

African (AFR) AF: 0.0614 AC: 2551 AN: 41514

American (AMR) AF: 0.0605 AC: 925 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0415 AC: 144 AN: 3468

East Asian (EAS) AF: 0.0607 AC: 313 AN: 5160

South Asian (SAS) AF: 0.123 AC: 596 AN: 4830

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10620

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0147 AC: 1002 AN: 68012

Other (OTH) AF: 0.0426 AC: 90 AN: 2114

Alfa AF: 0.00254 Hom.: 0

Bravo AF: 0.0417

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.18
DANN	Benign	0.39
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2289801; hg19: chr17-74467164; COSMIC: COSV51685022; COSMIC: COSV51685022;