Genetic Variant RHBDF2:c.*619A>G (chr17-76471014-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001005498.4(RHBDF2):c.*619A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0761 in 153,164 control chromosomes in the GnomAD database, including 929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.077 ( 929 hom., cov: 33)

Exomes 𝑓: 0.0095 ( 0 hom. )

Consequence

RHBDF2
NM_001005498.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.446

Publications

4 publications found

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 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)

RHBDF2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 17-76471014-T-C is Benign according to our data. Variant chr17-76471014-T-C is described in ClinVar as Benign. ClinVar VariationId is 325402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RHBDF2	NM_001005498.4	MANE Select	c.*619A>G	3_prime_UTR	Exon 19 of 19	NP_001005498.2	Q6PJF5-2
RHBDF2	NM_024599.5		c.*619A>G	3_prime_UTR	Exon 19 of 19	NP_078875.4	Q6PJF5-1
RHBDF2	NM_001376228.1		c.*619A>G	3_prime_UTR	Exon 19 of 19	NP_001363157.1	Q6PJF5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RHBDF2	ENST00000675367.1	MANE Select	c.*619A>G	3_prime_UTR	Exon 19 of 19	ENSP00000501790.1	Q6PJF5-2
RHBDF2	ENST00000313080.8	TSL:1	c.*619A>G	3_prime_UTR	Exon 19 of 19	ENSP00000322775.3	Q6PJF5-1
RHBDF2	ENST00000590168.5	TSL:1	n.2542A>G	non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes

AF:

0.0764

AC:

11621

AN:

152096

Hom.:

923

Cov.:

show subpopulations

Gnomad AFR

AF:

0.191

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0815

Gnomad ASJ

AF:

0.0516

Gnomad EAS

AF:

0.0618

Gnomad SAS

AF:

0.126

Gnomad FIN

AF:

0.00424

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0164

Gnomad OTH

AF:

0.0774

GnomAD4 exome

AF:

0.00947

AC:

AN:

950

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

AN XY:

488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.0189

AC:

AN:

106

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.167

AC:

AN:

South Asian (SAS)

AF:

0.0385

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00667

AC:

AN:

750

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0766

AC:

11654

AN:

152214

Hom.:

929

Cov.:

AF XY:

0.0759

AC XY:

5648

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.192

AC:

7957

AN:

41500

American (AMR)

AF:

0.0814

AC:

1244

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0516

AC:

179

AN:

3472

East Asian (EAS)

AF:

0.0620

AC:

321

AN:

5178

South Asian (SAS)

AF:

0.125

AC:

605

AN:

4822

European-Finnish (FIN)

AF:

0.00424

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0164

AC:

1117

AN:

68010

Other (OTH)

AF:

0.0780

AC:

165

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

490

980

1471

1961

2451

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0475

Hom.:

278

Bravo

AF:

0.0848

Asia WGS

AF:

0.0960

AC:

334

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Palmoplantar keratoderma-esophageal carcinoma syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.0

(source)

DANN

Benign

0.40

PhyloP100

-0.45

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over