Genetic Variant RHBDF1:p.Arg265Pro (chr16-62776-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_022450.5(RHBDF1):c.794G>C(p.Arg265Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R265Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RHBDF1
NM_022450.5 missense, splice_region

Scores

Splicing: ADA: 0.9781

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.66

Publications

0 publications found

Variant links:

Genes affected

RHBDF1 (HGNC:20561): (rhomboid 5 homolog 1) Predicted to enable growth factor binding activity and serine-type endopeptidase activity. Involved in several processes, including negative regulation of protein secretion; regulation of epidermal growth factor receptor signaling pathway; and regulation of proteasomal protein catabolic process. Located in Golgi membrane and endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

RHBDF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHBDF1	NM_022450.5 link	c.794G>C	p.Arg265Pro	missense_variant, splice_region_variant	Exon 6 of 18	ENST00000262316.10	NP_071895.3	Q96CC6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RHBDF1	ENST00000262316.10 link	c.794G>C	p.Arg265Pro	missense_variant, splice_region_variant	Exon 6 of 18	1	NM_022450.5	ENSP00000262316.5	Q96CC6
RHBDF1	ENST00000428730.5 link	n.*108G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 17	5		ENSP00000411508.1	F8WBS4
RHBDF1	ENST00000428730.5 link	n.*108G>C		3_prime_UTR_variant	Exon 5 of 17	5		ENSP00000411508.1	F8WBS4
RHBDF1	ENST00000417043.5 link	n.*724G>C		downstream_gene_variant		3		ENSP00000412218.1	F8WCF7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461720

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.040

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.065

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.3

PhyloP100

4.7

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.5

REVEL

Benign

0.24

Sift

Benign

0.14

Sift4G

Benign

0.18

Polyphen

0.79

Vest4

0.83

MutPred

0.25

Gain of loop (P = 0.0045);

MVP

0.72

MPC

0.55

ClinPred

0.94

GERP RS

4.7

Varity_R

0.41

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.78

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over