Variant 22-29260552-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000216085.12(RHBDD3):c.757T>C(p.Ser253Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 1,598,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

RHBDD3
ENST00000216085.12 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.529

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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.053904414).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHBDD3	NM_012265.3 linkuse as main transcript	c.757T>C	p.Ser253Pro	missense_variant	6/7	ENST00000216085.12	NP_036397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RHBDD3	ENST00000216085.12 linkuse as main transcript	c.757T>C	p.Ser253Pro	missense_variant	6/7	1	NM_012265.3	ENSP00000216085	P1
RHBDD3	ENST00000496342.1 linkuse as main transcript	n.796T>C		non_coding_transcript_exon_variant	3/3	2
RHBDD3	ENST00000413137.6 linkuse as main transcript	c.*333T>C		3_prime_UTR_variant, NMD_transcript_variant	6/7	5		ENSP00000399550

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000304

AC:

AN:

1446692

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

718666

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000370

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The c.757T>C (p.S253P) alteration is located in exon 6 (coding exon 4) of the RHBDD3 gene. This alteration results from a T to C substitution at nucleotide position 757, causing the serine (S) at amino acid position 253 to be replaced by a proline (P). 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

0.071

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

3.4

DANN

Uncertain

0.98

DEOGEN2

Benign

0.012

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.26

M_CAP

Benign

0.0075

MetaRNN

Benign

0.054

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.050

REVEL

Benign

0.0030

Sift

Benign

0.21

Sift4G

Benign

0.30

Polyphen

0.0

Vest4

0.11

MutPred

0.22

Gain of catalytic residue at S253 (P = 0.0058);

MVP

0.31

MPC

0.013

ClinPred

0.058

GERP RS

-3.5

Varity_R

0.037

gMVP

0.42

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over