Genetic Variant RHBDD3:p.Pro258Leu (chr22-29260536-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012265.3(RHBDD3):c.773C>T(p.Pro258Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000208 in 1,445,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RHBDD3
NM_012265.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.66

Publications

0 publications found

Variant links:

Genes affected

RHBDD3 (HGNC:1308): (rhomboid domain containing 3) Predicted to enable serine-type endopeptidase activity. Predicted to be involved in proteolysis. Predicted to act upstream of or within several processes, including liver development; negative regulation of natural killer cell activation; and positive regulation of protein catabolic process. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

RHBDD3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11918494).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHBDD3	NM_012265.3 link	c.773C>T	p.Pro258Leu	missense_variant	Exon 6 of 7	ENST00000216085.12	NP_036397.1	Q9Y3P4A0A024R1J2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RHBDD3	ENST00000216085.12 link	c.773C>T	p.Pro258Leu	missense_variant	Exon 6 of 7	1	NM_012265.3	ENSP00000216085.7	Q9Y3P4
RHBDD3	ENST00000413137.6 link	n.*349C>T		non_coding_transcript_exon_variant	Exon 6 of 7	5		ENSP00000399550.2	F8WFA9
RHBDD3	ENST00000496342.1 link	n.812C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2
RHBDD3	ENST00000413137.6 link	n.*349C>T		3_prime_UTR_variant	Exon 6 of 7	5		ENSP00000399550.2	F8WFA9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1445370

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717840

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.00

AC:

AN:

42310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25686

East Asian (EAS)

AF:

0.00

AC:

AN:

39336

South Asian (SAS)

AF:

0.00

AC:

AN:

83784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5616

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1106864

Other (OTH)

AF:

0.00

AC:

AN:

59914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.773C>T (p.P258L) alteration is located in exon 6 (coding exon 4) of the RHBDD3 gene. This alteration results from a C to T substitution at nucleotide position 773, causing the proline (P) at amino acid position 258 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.063

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.61

M_CAP

Benign

0.030

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

3.7

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.080

Sift

Uncertain

0.0080

Sift4G

Benign

0.28

Polyphen

0.0070

Vest4

0.18

MutPred

0.25

Loss of glycosylation at P258 (P = 0.0211);

MVP

0.49

MPC

0.014

ClinPred

0.33

GERP RS

4.4

Varity_R

0.053

gMVP

0.40

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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chr22-29260536-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over