chr17-76471301-A-AC

Variant names:

• chr17-76471301-A-AC
• rs58073681
• NM_001005498.4:c.*331dupG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001005498.4(RHBDF2):​c.*331dupG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 294,462 control chromosomes in the GnomAD database, including 463 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.040 (409 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (54 hom.)
• Consequence: RHBDF2 NM_001005498.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.07
• 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 -10 ACMG points.

• BP6: Variant 17-76471301-A-AC is Benign according to our data. Variant chr17-76471301-A-AC is described in ClinVar as Benign. ClinVar VariationId is 325411.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 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.*331dupG		3_prime_UTR	Exon 19 of 19	NP_001005498.2	Q6PJF5-2
	RHBDF2	NM_024599.5		c.*331dupG		3_prime_UTR	Exon 19 of 19	NP_078875.4	Q6PJF5-1
	RHBDF2	NM_001376228.1		c.*331dupG		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.*331dupG		3_prime_UTR	Exon 19 of 19	ENSP00000501790.1	Q6PJF5-2
	RHBDF2	ENST00000313080.8	TSL:1	c.*331dupG		3_prime_UTR	Exon 19 of 19	ENSP00000322775.3	Q6PJF5-1
	RHBDF2	ENST00000590168.5	TSL:1	n.2254dupG		non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes AF: 0.0404 AC: 6146 AN: 152094 Hom.: 407 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.0402

GnomAD4 exome AF: 0.00659 AC: 938 AN: 142250 Hom.: 54 Cov.: 0 AF XY: 0.00595 AC XY: 438 AN XY: 73568

African (AFR) AF: 0.126 AC: 639 AN: 5052

American (AMR) AF: 0.0135 AC: 75 AN: 5568

Ashkenazi Jewish (ASJ) AF: 0.00413 AC: 19 AN: 4606

East Asian (EAS) AF: 0.00 AC: 0 AN: 9492

South Asian (SAS) AF: 0.000232 AC: 3 AN: 12944

European-Finnish (FIN) AF: 0.000155 AC: 1 AN: 6432

Middle Eastern (MID) AF: 0.00794 AC: 5 AN: 630

European-Non Finnish (NFE) AF: 0.000796 AC: 71 AN: 89202

Other (OTH) AF: 0.0150 AC: 125 AN: 8324

GnomAD4 genome AF: 0.0405 AC: 6161 AN: 152212 Hom.: 409 Cov.: 33 AF XY: 0.0391 AC XY: 2912 AN XY: 74436

African (AFR) AF: 0.137 AC: 5681 AN: 41498

American (AMR) AF: 0.0204 AC: 312 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 68012

Other (OTH) AF: 0.0398 AC: 84 AN: 2112

Alfa AF: 0.0316 Hom.: 31

Bravo AF: 0.0472

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Palmoplantar keratoderma-esophageal carcinoma syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.1
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: rs58073681; hg19: chr17-74467383;